Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[C:20]2[CH2:21][C:22]([CH3:29])([CH3:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH2:25]2)[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(NC(C)=O)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
N-{4-[[4-(methyloxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetamide (57) (0.27 g, 0.69 mmol) was dissolved in CH2Cl2 (25 mL). The mixture was cooled to −10° C. in an ice-acetone bath. To this solution was added 1 M BBr3 in CH2Cl2 (2.1 mL, 2.07 mmol). The reaction mixture was stirred at −10° C. to 0° C. for 3 h, then poured onto ice, extracted with EtOAc (2×60 mL). The combined organic extract was washed with water, brine and dried over Na2SO4. Upon concentration and trituration with 1:1 hexanes:CH2Cl2, compound 58 was obtained as a light brown solid (0.10 g, 39%). mp 118-121° C. 1H NMR (400 MHz, DMSO-d6): δ 0.85 (s, 6H), 0.86 (s, 6H), 1.23 (s, 2H), 1.87 (s, 2H), 1.89 (s, 2H), 1.98 (s, 3H), 6.64 (d, J=8.3 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 9.24 (s, 1H), 9.84 (s, 1H); LCMS (ES): m/z 378 (M+H)+, 376 (M−H)−. Anal. Calcd for C25H31NO2.⅓H2O: C, 78.29; H, 8.32; N, 3.65. Found: C, 78.33; H, 8.26; N, 3.62.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]([OH:41])([CH3:40])[CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]([C:26]2[CH:31]=[C:30]([C:32]([NH:34][CH:35]4[CH2:37][CH2:36]4)=[O:33])[CH:29]=[CH:28][C:27]=2[CH3:38])[C:19]3=[O:39])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>CN(C=O)C>[CH:35]1([NH:34][C:32](=[O:33])[C:30]2[CH:29]=[CH:28][C:27]([CH3:38])=[C:26]([N:20]3[C:19](=[O:39])[C:18]4[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][C:13]([OH:41])([CH3:40])[CH2:12][N:48]5[CH2:52][CH2:51][CH2:50][CH2:49]5)[CH:17]=4)[N:22]=[CH:21]3)[CH:31]=2)[CH2:37][CH2:36]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(O)COc2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCC(C)(O)CN3CCCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of the crude 3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-2-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (0.2 g) in anhydrous DMF (10 ml) was added potassium carbonate (0.1 g) followed by pyrrolidine (0.15 g) and the mixture stirred at room temperature for 18 hours. The mixture was concentrated and purification by preparative HPLC provided the title compound as a gum (50 mg); NMR Spectrum: (CDCl3) 0.60 (m, 2H), 0.90 (m, 2H), 1.20 (m, 1H), 1.40 (s, 3H), 1.80 (m, 4H), 2.20 (s, 3H), 2.75 (m, 6H), 4.20 (m, 2H), 6.40 (s, 1H), 7.50 (m, 2H), 7.70 (m, 3F[), 7.80 (d, 1H), 7.90 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[O:4]1.[Na+].[I-].[C-:21]#[N:22].[K+].[Na].C([O-])(O)=O.[Na+].O>CS(C)=O>[C:21]([CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[O:4]1)#[N:22]
Reactant: [C-]#N
Reactant: COc1ccc(F)cc1CCC1CCC(CBr)O1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(F)cc1CCC1CCC(CC#N)O1
Temperature: 70 °C

Procedure:
To a vial under an atmosphere of Ar(g) was added 10 (1.23 g, 4.3 mmol), NaI (100 mg), potassium cyanide (0.7 g, 10.6 mmol), and dry DMSO (15 mL). The mixture obtained was heated to 70° C. under an atmosphere of Ar for 12 h. After cooling to room temperature, the reaction mixture was poured into a separatory funnel containing sodium bicarcarbonate aqueous solution (sat. NaHCO3/H2O, 50:50, v:v, 80 mL). The organic fraction was extracted with EtOAc (3×60 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The solvent was then removed in vacuo and the crude product obtained (0.45 g, 86%) was purified by flash column chromatography (EtOAc/hexane, 10:90, v:v, Rf=0.11); as a 2:1 mixture of trans/cis diastereomers. 1H NMR (500 MHz, CDCl3) δ 6.88-6.82 (m, 2 H), 6.74 (dd, J=4.3, 8.5 Hz, 1 H), 4.26 (m, 1 H), 4.09 (m, 0.65 H), 3.90 (m, 0.35 H) 3.79 (s, 3 H), 2.72-2.53 (m, 4 H), 2.22-2.04 (m, 2 H), 1.84-1.6 (m, 4 H).
Reaction SMILES: [CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6][CH2:7]2.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=1>>[CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([C:15]1[CH:14]=[N:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[CH2:6][CH2:7]2
Reactant: Clc1ccc(I)cn1
Reactant: CN1C2CCNCC1CC2
Product: CN1C2CCC1CN(c1ccc(Cl)nc1)CC2
Yield: 78 %

Procedure:
9-Methyl-3,9-diazabicyclo[4.2.1]nonane (prepared as described in U.S. Pat. No. 2,999,091) and 2-chloro-5-iodopyridine were coupled according the procedure of Example 15C to provide the title compound (78% yield). 1H NMR (free base, CDCl3, 300 MHz) δ 1.23-1.48 (m, 2H), 1.65-1.76 (m, 1H), 1.91-2.27 (m, 3H), 2.44 (s, 3H), 3.18-3.35 (m, 3H), 3.48-3.54 (m, 2H), 3.65 (br d, J=13.5 Hz, 1H), 6.98 (dd, J=3, 8.25 Hz, 1H), 7.06 (d, J=8.25 Hz, 1H), 7.87 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 252 (M+H)+, 269 (M+NH4)+; Anal. Calcd. for C13H18ClN3.C7H8O3S: C, 56.66; H, 6.18; N, 9.91. Found: C, 56.76; H, 6.15; N, 9.77.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O)=[CH:6][N:5]=[C:4]2[NH:16][CH:17]=[CH:18][C:3]=12.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[O:13][C:12]([O:14][CH3:15])=[CH:11][N:10]=2)=[CH:6][N:5]=[C:4]2[NH:16][CH:17]=[CH:18][C:3]=12
Reactant: COC(=O)CNC(=O)c1cnc2[nH]ccc2c1Cl
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cnc(-c2cnc3[nH]ccc3c2Cl)o1
Yield: 28.9 %

Procedure:
To a solution of methyl N-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonyl]glycinate (167 mg) in chloroform (5 ml) was added diphosphorus pentoxide (886 mg) under ambient temperature, and the mixture was refluxed for 18 hours. The reaction solution was cooled and added to saturated aqueous sodium hydrogencarbonate. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer silica gel column chromatography (chloroform:methanol=15:1) to obtain 4-chloro-5-(5-methoxy-1,3-oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (45 mg) as a yellowish white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:7]1=[CH:8][C:9]3[C:10](=O)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17](=O)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:26])[CH3:25].I.O.II>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:7]1=[CH:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:26])[CH3:25])[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1ccccc1C3=O
Agent: I
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)c2cc(Br)ccc2-c2cc3cc4ccccc4cc3cc21
Reaction time: 48 h
Yield: 60.5 %

Procedure:
2-bromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene-6,11-dione (20 g, 0.05 mol) was dissolved in acetic acid (200 ml), and added with 57% HI (50 ml), followed by reflux-stirring for 48 hours. After the reaction was completed, the resultant solution was added with distilled water (500 ml). The produced solid was filtered and dissolved in toluene (200 ml) and iodine (4.05 g, 0.016 mol) was added thereto, followed by reflux-stirring for 3 hours. After the reaction was completed, through extraction and column chromatography, 2-bromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene (11.3 g, yield 61%) was obtained.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[K+].Br[C:34]1[S:35][CH:36]=[CH:37][N:38]=1>C(N(CC)CC)C.C(#N)C>[CH3:10][C:7]1[S:6][C:5]([C:4]#[C:3][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(C#C[Si](C)(C)C)s1
Reactant: Brc1nccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C#Cc2nccs2)s1
Yield: 41.8 %

Procedure:
In a manner similar to Step E of Example 3, the reaction of 7.96 gram (0.0410 mole) of 1-trimethylsilyl-2-(5-methylthien-2-yl)ethyne, 1.23 gram (3.9×10-4 mole) of tetrabutylammonium fluoride, and 2.6 gram (0.045 mole) of potassium fluoride in 120 ml of triethylamine and 40 ml of acetonitrile with 6.39 grams (0.0390 mole) of 2-bromothiazole yielded 3.35 grams of 1-(5-methylthien-2-yl)-2-(thiazol-2-yl)ethyne as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30](=[O:32])[CH3:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]([OH:32])[CH3:31])=[O:22])=[CH:34][CH:35]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C(C)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-acetylphenyl)benzamide (200 mg) in methanol (15 ml) was added sodium borohydride (16.4 mg) and the solution was stirred at ambient temperature for 3 hours. Chloroform was added to the mixture and the solution was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give a syrup and the crude product was purified by silica gel column (chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(1-hydroxyethyl)phenyl]-benzamide (150 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN(C)C=O.C(OCC)(=O)C.O>[N:37]1([C:1]([C:4]2[CH:5]=[C:6]([N:10]3[C:14]4[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH:7]=[CH:8][CH:9]=2)=[O:3])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: C1COCCN1
Reactant: Cc1ccc2c(c1)ncn2-c1cccc(C(=O)O)c1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)ncn2-c1cccc(C(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(3-carboxyphenyl)-5-methylbenzimidazole (50 mg, 0.19 mM), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, HCl (76 mg, 0.39 mM), hydroxybenzotriazole (53 mg, 0.39 mM) in dimethylformamide (2 ml) was treated with triethylamine (80 μl, 0.39 mM) and morpholine (20 μl, 0.22 mM) and the reaction stirred for 18 hours at room temperature under N2. Dilution with water and extractive work up with ethyl acetate was followed by chromatography on silica gel. Yield 37 mg. 1H NMR (360 MHz, DMSO) 2.51 (3H, s), 3.47-3.73 (8H, m), 7.16 (1H, d, J=8.3 Hz), 7.41 (1H, d, J=8.3 Hz), 7.45 and 7.47 (1H, dt, J=1.4 Hz, 7.0 Hz), 7.57-7.60 (3H, m), 7.66 (1H, s) and 8.08 (1H, s). MS M+ 322.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[C:5]([O:14][CH3:15])=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([NH:20][NH:21][C:22](=[O:37])[CH:23]([C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)[CH2:24][CH2:25][CH2:26][Cl:27])=O>P(Cl)(Cl)(Cl)=O>[Cl:27][CH2:26][CH2:25][CH2:24][CH:23]([C:22]1[O:37][C:18](/[CH:17]=[CH:16]/[C:3]2[CH:4]=[C:5]([O:14][CH3:15])[C:6]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[CH:7][C:2]=2[F:1])=[N:20][N:21]=1)[C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2cc(F)c(F)c(F)c2)c(F)cc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nnc(C(CCCCl)c3cc(F)c(F)c(F)c3)o2)c(F)cc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid N′-{(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (200 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for 5.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 180 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:10][O:9][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[N:1]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:8]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sccc1N
Product: COC(=O)c1sccc1N=CN(C)C
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of methyl 3-amino-2-thiophenecarboxylate (1.572 g, 10 mmol) in 5 ml of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was heated at reflux for 2 h and then allowed to cool to room temperature. The resulting mixture was evaporated to give 2.019 g (95%) of orange residue. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.63 (d, J=5.6 Hz, 1H), 6.81 (d, J=5.2 Hz, 1H), 3.67 (m, 3H), 3.00 (s, 3H), 2.93 (s, 3H); LC-MS (ESI) m/z 213.1 (M+1).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:53][C:54]1[C:59]([CH3:60])=[CH:58][CH:57]=[CH:56][C:55]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:65]2[CH2:66][CH2:67][CH:62]([NH:61][C:55]3[CH:56]=[CH:57][CH:58]=[C:59]([CH3:60])[C:54]=3[CH3:53])[CH2:63][CH2:64]2)=[O:12])=[CH:5][CH:6]=1
Reactant: Cc1cccc(NC2CCNCC2)c1C
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC2CCN(C(=O)CC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.101 g, 0.00039 mole) in DMF (3 mL) was added DIPEA (0.233 g, 0.0018 mole), HOBt (0.053 g, 0.00039 mole) and EDCI.HCl (0.138 g, 0.00072 mole). After 2 minutes (2,3-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (1% methanol in chloroform) afforded 0.07 g (44%) of N-biphenyl-4-yl-3-[4-(2,3-dimethyl-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 442.24 (M+1)+, 95.5%, 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 7.7 (m, 6H), 7.6 (t, 2H), 7.4 (d, 1H), 6.8 (t, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 4.4 (t, 2H), 4.0 (d, 1H), 3.6 (bs, 3H), 3.2 (t, 1H), 2.8 (t, 1H), 2.2 (s, 3H), 2.0 (bs, 5H), 1.5 (d, 1H), 1.4 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[CH2:32]([NH:39][C:40](=[O:43])[CH2:41]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:41][C:40]([NH:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:43])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: O=C(CCl)NCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Product: COC(=O)[C@H](Cc1ccc(OCC(=O)NCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared by alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with N-benzyl-2-chloroacetamide (potasium carbonate, sodium iodide, refluxing butanone under Argon overnight). The product was purified by flash column chromatography (silica, 1:1 hexane:EtOAc) to afford the methyl ester as a white solid, mp 57-59° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[CH:3]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][Si:14]([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(Br)cc(O)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(O[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-6-methylpyridin-2-ol (376 mg, 2 mmol) in dry DMF (20 mL) is stirred under N2. TBDMS-Cl (600 mg, 4 mmol) is added, followed by triethylamine (0.97 mL, 7.00 mmol), and the mixture is stirred at rt for 1 h. The solution is poured into ice-water (170 mL) and extracted with diethyl ether (5×50 mL). The combined extracts are dried over Na2SO4 and the solvent is evaporated under reduced pressure. The residue is taken up in pentane (50 mL), dried over Na2SO4 and the solvent evaporated again, to afford the crude title compound as a yellow oil. This is used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([O:19]CC)=O)=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O)C.[ClH:22].[NH2:23][C:24]([NH2:26])=[NH:25].C[O-].[Na+]>CN(C)C=O.CO>[ClH:22].[ClH:22].[NH:25]([C:4]([C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([NH:25][C:24]([NH2:26])=[NH:23])=[O:19])=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:3])[C:24]([NH2:26])=[NH:23]
Reactant: N=C(N)N
Reactant: CCOC(=O)C1=Cc2cccc(C(=O)OCC)c2OCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N=C(N)NC(=O)C1=Cc2cccc(C(=O)NC(=N)N)c2OCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a mixture of ethyl 2,3-dihydro-9-ethoxycarbonyl-1-benzoxepin-4-carboxylate (0.10 g) and guanidine hydrochloride (0.33 g) in N,N-dimethylformamide (2 ml) was added 28% sodium methoxide in methanol (0.66 ml) at room temperature. After the mixture was stirred at room temperature overnight, it was purified by column chromatography on silica gel using a mixture of chloroform and methanol (30:1 to 4:1). The fractions containing objective compound was collected and evaporated in vacuo. The residue was treated with methanol and 4N hydrogen chloride in 1,4-dioxane, and the solvent was evaporated in vacuo. The residue was triturated with ethanol to give (2,3-dihydro-9-guanidinocarbonyl-1-benzoxepin-4-carbonyl)guanidine dihydrochloride (46 mg).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[K+].Cl>C1COCC1>[Cl:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(Cl)sc1-c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc(Cl)sc1-c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-chloro-5-phenylthiazole-4-carboxylate in THF was added a 1 M aqueous KOH solution, followed by stirring at 60° C. for 30 minutes. To the reaction mixture was added 1 M hydrochloric acid, and the solid precipitated was collected by filtration to obtain 2-chloro-5-phenylthiazole-4-carboxylic acid as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8]C(C2ON=C(C(C)(C)C)C=2)=O)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(Br)ccc2[N+](=O)[O-])on1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1nc(-c2ccccc2C(F)(F)F)ccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide (139 mg, 0.377 mmol, prepared as described in the previous step) in DME (15 mL) and water (5 mL) was treated with 2-trifluoromethylphenylboronic acid (85.8 mg, 0.452 mmol) and cesium carbonate (245 mg, 0.753 mmol). The resulting mixture was de-gassed via sonication, placed under Ar, treated with PdCl2(dppf).DCM (15.4 mg, 0.019 mmol), and heated to 80° C. for 18 h. The cooled mixture was diluted with water (50 mL) and extracted twice with EtOAc (50 mL, 25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 3:17 v/v over 40 min) to yield 6-(2-trifluoromethyl-phenyl)-3-nitro-pyridin-2-ylamine as a yellow solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C12H8F3N3O2: 284.1 (M+H). Measured: 284.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([Cl:63])[C:58]=2[F:64])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([Cl:63])[C:58]=2[F:64])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2F)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(Cl)c2F)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.7 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 96 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-chloro-2-fluoro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 4.5 h at rt, the reaction mixture was diluted with 50 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 107 mg white solid (68%). MS (ISP) 498.0 (M+H)+.