Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH:3]=1.[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C(O)=O>C(O)C.CC(O)C>[CH3:7][N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:16]2[N:15]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)[CH2:3]1
Reactant: Clc1nc2ccccc2n1Cc1ccccc1
Reactant: CN1C=C(N)CC1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: CN1CCC(Nc2nc3ccccc3n2Cc2ccccc2)C1
Temperature: 125 °C

Procedure:
To 14 g (0.14 mol) of 3-amino-N-methyl pyrroline was added 10.4 g (0.042 mol) of N-benzyl-2-chlorobenzimidazole and the reaction mixture heated to 125° C. for 2 days. The reaction mixture was partitioned between 150 mL of 1N NaOH and 100 mL of CH2Cl2. The aqueous layer was extracted again with 100 mL of CH2Cl2. The combined organic layers were washed with 100 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation and subjected to high vacuum at 100° C. for ~30 min. For purification, the residue was treated with 2 moles of oxalic acid in ethanol/2-propanol to afford 15 g (73%) of white analytically pure crystals, mp 211°-213° C. dec.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1.O>CN(C=O)C>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:19][N:18]=1)#[N:21]
Reactant: COc1ccc(CO)cc1
Reactant: N#Cc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C#N)nc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
Sodium hydride (1.44 g, 33 mmol) was dissolved in DMF (20 mL), and 4-methoxybenzyl alcohol (3.74 mL, 33 mmol) was then added to the solution under a nitrogen atmosphere and under ice cooling. The obtained mixture was stirred at room temperature for 30 minutes. Thereafter, 5-bromo-2-cyanopyridine (4.58 g, 25 mmol) was added to the reaction solution, and the obtained mixture was further stirred at room temperature for 30 minutes. Thereafter, water was added to the reaction solution, and it was then extracted with ethyl acetate and washed with water. The water layers were combined and extracted with methylene chloride. The organic layers were combined, were dried over sodium sulfate, and were then concentrated. The obtained residue was recrystallized from ethyl acetate, so as to obtain the title compound (3.57 g, yield: 60%) in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1I.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.CCOCC>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:7]2[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=2[Cl:1])[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1ccc(I)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2Cl)CC1
Temperature: 100 °C
Yield: 10 %

Procedure:
A mixture of 0.5 g (1.6 mmol) of 3-chloro-4-iodobenzotrifluoride 0.7 g (3.8 mmol), N-Boc-piperazine, 41 mg (0.04 mmol) Tris(dibenzylideneacetone)dipalladium chloroform complex, 0.44 g (4.43 mmol) sodium-t-butoxide and 48 mg (0.16 mmol) tri-o-tolylphosphine in 6 ml dioxane was heated overnight at 100° C. The solution was allowed to cool to room temperature, taken up in ether (30 ml) and washed with brine (25 ml). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over on silica gel: Eluent: Heptane-AcOEt 0-10% over 15 min to provide the title compound (0.06 g, 10%) as a brown oil, MS (m/e): 365.1 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][CH:6]1[C:7]([CH2:16][O:17][CH3:18])=[CH:8][C@H:9]2[CH2:14][OH:15])[CH:2]=[CH2:3].I[CH3:20].[Al]>C(#N)C.[Ag]=O>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][CH:6]1[C:7]([CH2:16][O:17][CH3:18])=[CH:8][C@H:9]2[CH2:14][O:15][CH3:20])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCON1C(=O)N2CC1C(COC)=C[C@H]2CO
Agent: O=[Ag]
Agent: [Al]
Solvent: CC#N
Product: C=CCON1C(=O)N2CC1C(COC)=C[C@H]2COC
Yield: 31.6 %

Procedure:
To a stirred solution of Intermediate 123 (0.3 g, 1.18 mmol) in ACN (12 mL) was added iodomethane (0.734 mL, 11.80 mmol) and silver oxide (1.094 g, 4.72 mmol). The reaction was stirred at rt with aluminum foil wrapped around overnight. LCMS showed product. The mixture was filtered and concentrated. The residue was then purified by silica gel column (40 g, 0-100% Hex/EA) to afford the title compound (0.100 g, 31.6%) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.[NH:18]1[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]1.C([O-])(=O)C.[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]3=[C:2]([N:18]3[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccsc23)CC1
Temperature: 160 °C
Yield: 59.5 %

Procedure:
A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (68 mg, 0.26 mmole), isonipecotamide (66 mg, 0.52 mmole), and sodium acetate (21 mg, 0.26 mmole) in 1-methyl-2-pyrrolidone (3 mL) is stirred and heated in an oil bath at 160° C. for about 4 hours. The reaction mixture is then cooled, diluted with ethyl acetate (15 mL) and washed with water (3×15 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is recrystalized with ethyl acetate to give 1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide (55 mg, 60% yield) as a white solid product (m.p. 251° C.-253° C.).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1>>[CH3:12][C:4]1[C:5]([C:9]([N:18]2[CH2:17][C@H:16]([CH3:20])[NH:15][C@H:14]([CH3:13])[CH2:19]2)=[O:11])=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Yield: 72.1 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g, 11.96 mmol) reacted with cis-2,6-dimethylpiperazine (2.66 g, 14.36 mmol) to give 2.27 g (72%) of 3,5-dimethyl-4-[(3R,5S)-3,5-dimethyl-piperazine-1-carbonyl]-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound. HR-MS (ES, m/z) calculated for C36H45N4O3Cl2 [(M+H)+] 651.2863, observed 651.2863.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][NH:13][C:12](=[O:15])[C@H:11]([NH:16]C(=O)OCC3C=CC=CC=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>[Pd].C1(C)C=CC=CC=1.CO>[NH2:16][C@@H:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:14][NH:13][C:12]1=[O:15]
Reactant: O=C(N[C@@H]1CC=C(c2ccc(O)cc2)CNC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: N[C@@H]1CCC(c2ccc(O)cc2)CNC1=O
Reaction time: 18 h

Procedure:
10% Palladium on carbon (10 mg) was added to a solution of benzyl (3R)-6-(4-hydroxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (15 mg, 0.043 mmol) in toluene (5 mL) and methanol (1 mL). The reaction vessel is evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated. MS 221 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C(=O)C)=[CH:14][CH:13]=1.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27](Cl)=O>>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:27][NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1
Reactant: COc1ccc(C=Cc2ccc(OC(C)=O)cc2)c(N)c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: Cl
Product: COc1ccc(C=Cc2ccc(O)cc2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 67.6 %

Procedure:
Synthesized from acetic acid 4-[2-(2-amino-4-methoxyphenyl)vinyl]phenyl ester (240 mg) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (660 mg) according to an analogous synthetic method to Example 152, the title compound (273 mg) was obtained.
Reaction SMILES: [Na].Br[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(OCC)C.[Cl-].[Na+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:3]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Reaction time: 2 h
Yield: 47.5 %

Procedure:
7.05 g of sodium were dissolved in a solution of 49 g of diethyl malonate in 175 ml of ethanol. The still warm solution (50° C.) was treated dropwise within 15 minutes with 45.6 g of 5-bromo-1-pentene and the mixture was heated to boiling for 2 hours. After cooling the reaction mixture was poured into 500 ml of diethyl ether and 300 ml of semi-saturated sodium chloride solution. The aqueous phase was separated and back-extracted twice with 200 ml of diethyl ether each time. The organic phases were washed twice with 150 ml of semi-saturated sodium chloride solution each time, dried over sodium sulphate, filtered and concentrated. Chromatographic separation of the resulting, yellow liquid (55.2 g) on silica gel with hexane/ethyl acetate (vol. 95:5) gave 33.2 g of diethyl (4-pentenyl)-malonate as a colourless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:3]=1.[S:11](Cl)([CH3:14])(=[O:13])=[O:12]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:14][S:11]([O:10][CH:8]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=1)[CH3:9])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc(Br)ccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1cc(Br)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirring solution of the 1-(4-bromopyridin-2-yl)ethanol (3.72 g, 18.41 mmol and DMAP (4.5 g, 36.82 mmol) in 75 mL of dichloromethane was cooled to 0° C. To it was added mesyl chloride (1.71 mL, 22.09 mmol) dropwise. The mixture was stirred at 0° C. for 10 minutes, then warmed to room temperature and stirred for 15 min. The reaction was quenched with 50 mL ice water, the layers were separated, and the aqueous layer was extracted with dichloromethane (50 mL). The organics were combined, washed with water and brine, dried over Na2SO4, and purified by column chromatography (gradient 0 to 45% EtOAc/hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=5.3 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.45 (dd, J=5.3, 1.8 Hz, 1H), 5.75 (q, J=6.6 Hz, 1H), 3.00 (s, 3H), 1.75 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][C:14]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[C:18]([B:29]2[O:33][C:32](C)(C)C(C)(C)[O:30]2)[C:15]=1C=O>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:32]1[O:33][B:29]([OH:30])[C:18]2[CH:19]=[C:20]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=[C:14]([CH3:13])[C:15]1=2)[CH3:12]
Reactant: Cc1cc(Oc2ccccc2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccccc3)cc(C)c21
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
A suspension of zinc dust (1.26 g, 19.30 mmol) in THF (8 mL) was treated with chlorotrimethylsilane (0.30 mL, 2.40 mmol) at 40° C. The mixture was heated at 55° C. for 15 minutes, the cooled to 37° C. Ethyl bromoacetate (1.68 mL, 17.70 mmol) was added dropwise (refluxed gently upon addition), then stirred for 5 min. The suspension was allowed to settle at room temperature. The Reformasky reagent (approximately 1.7 M stock solution, 1.5 mL, 2.55 mmol) was transferred via syringe to a dry flask, then cooled to 0° C. 2-Methyl-4-phenoxy-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (0.50 g, 1.48 mmol) in THF (5 mL) was added dropwise to the reagent, then stirred at 0° C. for 4 h. The mixture was quenched with saturated NH4Cl, extracted with EtOAc, dried (Na2SO4), filtered and concentrated to a yellow oil. The oil was purified by column chromatography (SiO2, EtOAc/hexanes; 1:5 to 1:1 gradient) to afford (1-hydroxy-4-methyl-6-phenoxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.22 g, 46%), as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.40 (t, J=7.42 Hz, 2H), 7.16 (t, J=7.42 Hz, 1H), 7.07 (d, J=2.35 Hz, 1H), 7.02-6.97 (m, 3H), 5.51 (dd, J=9.33, 2.34 Hz, 1H), 4.05 (q, J=7.03 Hz, 2H), 3.14 (dd, J=15.63, 2.74 Hz, 1H), 2.89 (s, 3H), 2.33-2.26 (m, 1H), 1.14 (t, J=7.03 Hz, 3H); MS (ES) m/z: 325 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2cnc3c(N)ncnc32)cc1
Yield: 89.2 %

Procedure:
In 1,000 mL of methanol, 13.1 g (51 mmol) of [9-(4-nitrophenyl)-9H-purin-6-yl]amine was suspended, and 1.0 g of 10% palladium carbon was added thereto and the mixture suspension was stirred at 60° C. for 22 hours in a hydrogen atmosphere. The palladium carbon was removed by Celite filtration and the filtrate was washed with 3 L of hot methanol. The methanol solution was concentrated under reduced pressure and the formed product was purified by a silica gel column (ethyl acetate:methanol=8:1) to obtain 10.29 g (89%) of a target product as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[CH2:5][N:6]1[C:11](=[O:12])[CH2:10][N:9]([C:13](=[O:22])[CH2:14][O:15][C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:8][CH:7]1[C:23]([OH:25])=[O:24].[N:31]1C=NC=N[CH:32]=1.CC(O)=O>CCO>[NH2:30][C:29]1[C:28]2[C:2](=[CH:3][C:4]([CH2:5][N:6]3[C:11](=[O:12])[CH2:10][N:9]([C:13](=[O:22])[CH2:14][O:15][C:16]4[S:17][C:18]([Cl:21])=[CH:19][CH:20]=4)[CH2:8][CH:7]3[C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[N:1]=[CH:32][N:31]=1
Reactant: N#Cc1ccc(CN2C(=O)CN(C(=O)COc3ccc(Cl)s3)CC2C(=O)O)cc1N
Reactant: c1ncncn1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ncnc2cc(CN3C(=O)CN(C(=O)COc4ccc(Cl)s4)CC3C(=O)O)ccc12
Yield: 105.1 %

Procedure:
A solution containing (+/−)-1-(3-amino-4-cyano-benzyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid (20 mg, 0.03 mmol), 1,3,5-triazine (28 mg, 0.34 mmol), and glacial HOAc (20 mg, 0.34 mmol) in absolute EtOH (6 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated to dryness and then purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 15 mg (75%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.75-4.38 (m, 5H), 4.67 (d, J=14.8 Hz, 1H), 4.79 (d, J=15.3 Hz, 1H), 4.95 (m, 1H), 5.09 (br d, J=16.0 Hz, 1H), 6.18 (m, 1H), 6.71 (m, 1H), 7.64 (m, 2H), 8.31 (d, J=8.5 Hz, 1H), 8.75 (s, 1H), 9.64 (br s, 2H) ppm; MS (ISP loop): m/z 476 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2([C:30]#N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1)C1C=CC=CC=1>O1CCCC1.BrCCBr>[CH2:11]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2([C:30]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:22][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(N2CCN(Cc3ccccc3)CC2)CCCCC1
Reactant: Brc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: c1ccc(CN2CCN(C3(c4ccccc4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To bromobenzene (0.6 g) and magnesium turnings (0.2 g) in 30 ml dry tetrahydrofuran under nitrogen was added a small crystal of iodine and 10 drops of 1,2-dibromoethane. After small bubbles began to form, the reaction was stirred and heated to reflux for 4 hours. After cooling to room temperature, 1-benzyl-4-(1-cyanocyclohexyl)piperazine (1 g) was added. After 23 hours, the reaction was filtered, 20 ml saturated aqueous ammonium chloride was added and the mixture was extracted with diethyl ether. The ether was dried and removed in vacuo. The residue was chromatographed on silica gel eluted with chloroform to yield pure 1-benzyl-4-(1-phenylcyclohexyl)piperazine.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](=[O:9])[CH3:8])=[CH:3][CH:2]=1.[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:11][CH2:8][C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C(=O)CBr)cc1
Yield: 83.5 %

Procedure:
To a solution of 1-p-tolyl-ethanone (0.5 g, 4.16 mmol) in dichloromethane-methanol (50 ml-20 mL) was added tetrabutylammonium tribromide (2.2 g, 4.58 mmol) at room temperature. The mixture was stirred until the orange color faded. The solvent was then distilled under reduced pressure and the resulting precipitate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated in vacuo to give a residue which was purified by flash column chromatography to yield the desired product 2-bromo-1-p-tolyl-1-ethanone (0.74 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 2.39 (s, 3H), 4.89 (s, 2H), 7.37 (d, 2H), 7.89 (d, 2H); ESI-MS (MK): 213 and 215.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[C:17](I)[C:16]([OH:20])=[C:15](I)[CH:14]=1>COCCOC.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]([OH:20])=[C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1
Reactant: COC(=O)c1cc(I)c(O)c(I)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a stirred solution of phenylboronic acid (4.95 g, 40.57 mmol), Ba(OH)2.H2O (10.48 g, 55.33 mmol), and Pd(OAc)2 (0.414 g, 1.84 mmol) in DME/H2O (110 mL/20 mL) was added 3,5-diiodo-4-hydroxybenzoic acid methyl ester (7.45 g, 18.44 mmol). The mixture was stirred at 85° C. for 3 h and was then cooled and concentrated. The residue was partitioned between ethyl acetate/2N HCl. The organic phase was dried (MgSO4) and concentrated to give a solid which was triturated with diethyl ether/petroleum ether to give 3.51 g (62.5%) of product as a white solid. 1H NMR (DMSO-d6) δ 9.27 (s, 1H), 7.27 (s, 2H), 7.25-7.40 (m, 10H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1ccc2cccnc2c1
Solvent: C1CCOC1
Product: Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-methylquinoline (1.63 g, 11.4 mmol) in dry THF (10 mL), cooled by ice/water, is added phenyllithium (1.9M in cyclohexane/ether 70/30, 6.0 mL, 11.4 mmol) dropwise over 5 min. After 15 min, the cooling bath is removed, and the solution is stirred at rt for 5 h. The reaction is quenched by adding MeOH, and stirring is continued overnight. Water is added, the mixture is extracted with EtOAc (3×35 mL), and the combined extracts are dried over MgSO4. The drying agent is filtered off, and air is bubbled into the solution for 7 d. The solvent is evaporated; the residue is dissolved in warm (≈50° C.) EtOAc/hexanes and filtered warm. The filtrate is concentrated and dried in vacuo to obtain the crude title compound that is used directly for the next step. Further purification is possible by chromatography on silica gel (Jones Flashmaster, eluting with hexanes: EtOAc 3:1→2:1→1:1). 1H NMR(CDCl3, 400MHz) δ 2.58 (s, 3H), 7.31 (d, J=3.7 Hz, 1H), 7.36-7.49 (m, 1H), 7.52 (t, J=8.0 Hz, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.96 (s, 1H), 8.16 (t, J=8.0 Hz, 2H). MS (ES+): m/z 220.3 (100) [MH+]. HPLC: tR=2.7 min (Platform II, nonpolar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl.Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)O)cc23)ccn1
Temperature: 23 °C
Reaction time: 0.83 h
Yield: 85.2 %

Procedure:
The synthetic intermediate from Step 1 (392 mg, 0.791 mmol), dichloromethane (2 ml), and trifluoroacetic acid (2 ml) were combined in an open vial. Triethylsilane (1.011 ml, 6.33 mmol) was then added, and the resulting mixture was stirred at a temperature of 23° C. for 50 minutes. The reaction mixture was then diluted with dichloromethane, and 2N HCl was added drop-wise until the pH of the mixture was between 4 and 5. This resulting precipitate was collected via filtration and rinsed with water, methanol and dichloromethane to afford 3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxylic acid (220 mg, 0.674 mmol, 85% yield) as a green solid. The crude product was progressed to the next step without purification.