Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[CH:7]1)[CH3:2].C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH2:1]([O:3][C:4](=[O:12])[C:5]([N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[CH:7]1)=[CH:16][N:17]([CH3:19])[CH3:18])[CH3:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1cnc(C)c1
Product: CCOC(=O)C(=CN(C)C)n1cnc(C)c1

Procedure:
310 mg (1.5 mmol, 80% purity) of the compound from Example 34A and 0.5 ml (434 mg, 3.0 mmol) dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 16 h. For working up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried in vacuo. The product is obtained as a 3:2 mixture of the two regioisomers and is further reacted as such.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1.[CH:26](=O)[CH3:27].Cl.[BH4-].[Na+]>CO.O>[ClH:22].[CH2:26]([NH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1)[CH3:27]
Reactant: CC=O
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.5 g of 1-(4-amino-2-chlorobenzoyl)-4-[2-(4-chlorophenyl)ethyl]-piperazine (see Example 7) are dissolved together with 0.26 g of acetaldehyde and 0.8 ml of 5N alcoholic hydrochloric acid in 15 ml of methanol. 0.41 g of 85% NaBH4 is added thereto and the reaction solution is stirred at room temperature for 24 hours. Water is added to the reaction solution, which is then decanted off and taken up in methylene chloride, dried and concentrated by evaporation. The oily material is chromatographed on silica gel and converted into the hydrochloride, yielding 1-[4-(N-ethylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine hydrochloride having a melting point of 230°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:17]=2[O:25][CH3:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[O:25][CH3:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc([N+](=O)[O-])cc1C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N)cc1CCc1cccc(NC(=O)OC(C)(C)C)c1
Yield: 94.5 %

Procedure:
tert-Butyl{3-[(2-methoxy-5-nitrophenyl)ethynyl]phenyl}carbamate (63 mg, 0.17 mmol) and 10% palladium on carbon (122 mg, 0.10 mmol) were stirred in N,N-dimethylformamide (3.0 mL) under an atmosphere of hydrogen for 16 hours. The mixture was diluted with ethyl acetate (9.0 mL) and filtered through celite. Evaporation of the filtrate gave the desired compound (55 mg, 94%). LCMS for C20H27N2O3 (M+H)+: m/z=343.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36]C1C=CC2C(=O)C(Br)=C(C3C=CC=CC=3)OC=2C=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]([NH2:36])=[CH:28][C:21]=4[O:20][C:19]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=O)cc2)CCC1
Reactant: Nc1ccc2c(=O)c(Br)c(-c3ccccc3)oc2c1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(N)ccc4c3=O)cc2)CCC1
Yield: 19 %

Procedure:
Following the procedure used for {1-[4-(4-oxo-2-phenyl-4H-1-benzopyran-3-yl)phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-amino-3-bromo-2-phenyl-1-benzopyran-4-one (28.4 mg, 0.09 mmol) was reacted to give the title compound as a yellow solid (6.3 mg, 19%). 1H-NMR (400 MHz, CDCl3) δ 8.05 (d, 1H), 7.64 (d, 2H), 7.50 (d, 2H), 7.45 (d, 2H), 7.35 (dd, 1H), 7.31 (dd, 2H), 6.82 (d, 1H), 6.74 (s, 1H), 5.28 (bs, 1H), 4.11 (bs, 2H), 2.62-2.65 (m, 4H), 2.15-2.19 (m, 1H), 1.90-1.97 (m, 1H) 1.33 (bs, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:14][C:13]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl.O>[C:30]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:24]=[CH:25][C:26]([CH2:28][CH3:29])=[CH:27][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:23])[CH:14]=1)[CH2:19][CH2:20][CH2:21][NH2:22])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(Oc2ccc(NCCCN)cc2F)c(OCc2ccccc2)c1
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (60 mg, 0.15 mmol) in 10 ml of dry dichloromethane, cooled to 0° C., was added acetic anhydride (20 mg, 0.19 mmol) taken in 0.5 ml of dichloromethane dropwise. The reaction mixture was warmed to rt and stirred for 1 h until reaction was complete on TLC. The reaction mixture was diluted with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined dichloromethane fraction was dried over anhydrous Na2SO4 and concentrated. The crude residue obtained was column purified over silica gel using 2% methanol in dichloromethane as eluant to get 50 mg, 75.4% of title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[CH:18]=[C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:21][C:16]=3[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:27][CH:28]([F:30])[F:29])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[Br-].[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][Zn+])[CH3:33].O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:29][CH:28]([F:30])[O:27][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][C:17]=1[CH:8]([C:4]1[CH:3]=[C:2]([CH2:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:39])[CH:7]=[CH:6][CH:5]=1)[O:9]2
Reactant: CCOC(=O)CC[Zn+]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(c1cccc(Br)c1)Oc1cccc(OC(F)F)c1-2
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCc1cccc(C2Oc3cccc(OC(F)F)c3-c3ccc(NS(C)(=O)=O)cc32)c1

Procedure:
A solution of Example 103 (0.05 g, 0.10 mmol), tetrakis(triphenylphosphine) palladium(O) (0.01, 0.01 mmol), and 3-ethoxy-3-oxopropylzincbromide (0.6 ml of 0.5M solution in THF) in THF (2 mL) was shaken in a sealed tube at 80° C. for 15 hours, treated with water (2 mL), and extracted with ethyl acetate. The extract was the concentrated and the residue was purified by high throughput HPLC with aqueous 0.1% TFA and CH3CN to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.17 (d, J=9 Hz, 1H), 6.52-7.74 (m, 10H), 6.31 (s, 1H), 4.18 (q, J=7 Hz, 2H), 3.02 (s, 3H), 1.25 (t, J=7 Hz, 3H); MS (ESI(−)Q1MS m/z 516 (M−H).
Reaction SMILES: [C:1]12([CH2:8][O:9][C:10]3[C:22](Cl)=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([F:24])[CH:11]=3)C[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[CH:25]12[CH2:30][CH:29]1CC(COC1C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=1)C2>>[CH:5]12[CH2:4][CH:3]1[CH2:2][CH:1]([CH2:8][O:9][C:10]1[C:22]([CH:25]3[CH2:30][CH2:29]3)=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[C:12]([F:24])[CH:11]=1)[CH2:6]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CC3CC3C2)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-2-fluorobenzoate, the title compound was obtained as a colourless solid (1.20 g, 70% yield): 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J=8.4 Hz, 1H), 6.43 (d, J=12.7 Hz, 1H), 3.78 (d, J=7.4 Hz, 2H), 2.88-2.74 (m, 2H), 2.16-2.07 (m, 1H), 1.98-1.89 (m, 1H), 1.55 (s, 9H), 1.50 (d, J=4.5 Hz, 1H), 1.46 (d, J=4.5 Hz, 1H), 1.30-1.25 (m, 2H), 0.88-0.82 (m, 2H), 0.58-0.53 (m, 2H), 0.09-0.05 (m, 1H); MS (ES+) m/z 369.1 (M+23).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([N:12]1[CH2:17][C:16](=[O:18])[N:15](C(=O)C)[CH2:14][C:13]1=[O:22])(=[O:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:9]([N:12]1[CH2:17][C:16](=[O:18])[NH:15]/[C:14](=[CH:1]\[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)/[C:13]1=[O:22])(=[O:11])[CH3:10]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)N1CC(=O)N/C(=C\c2ccccc2)C1=O

Procedure:
To a solution of benzaldehyde 4 (0.54 g, 5.05. mmol) in DMF (5 mL) was added compound 1 (2.0 g, 10.1 mmol) and the solution was repeatedly evacuated in a short time to remove oxygen and flushed with Ar, followed by the addition of Cs2CO3 (1.65 g, 5.05 mmol) and the evacuation-flushing process was repeated again. The resultant mixture was stirred for 3.5 h at room temperature. After the solvent was removed by evaporation, the residue was dissolved in the mixture of EtOAc and 10% Na2CO3, and the organic phase was washed with 10% Na2CO3 again and saturated NaCl for three times, dried over Na2SO4 and concentrated in vacuo. The residual solid was recrystalized from MeOH-ether to obtain a off-white solid of 17; yield 1.95 g (79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:20])([F:19])[C:12]3[N:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[N:9][N:10]=2)[CH:7]=1.Br[CH2:22][C:23](=O)[C:24]([O:26][CH3:27])=[O:25].C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:20])([F:19])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[N:18]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: COC(=O)C(=O)CBr
Reactant: Nc1ccc(C(F)(F)c2nnc3ccc(Br)cn23)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Temperature: 80 °C

Procedure:
A reaction mixture of 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)pyridazin-3-amine (11.0 g, 32.2 mmol), methyl 3-bromo-2-oxopropanoate (11.67 g, 64.5 mmol), and NaHCO3 (10.84 g) in dioxane (150 mL) was heated at 80° C. for 4 hrs to provide a red reaction mixture. Solids were filtered off, rinsed with dioxane, and the combined filtrates were concentrated via rotary evaporation. The resulting residue was dissolved in EtOAc and washed with 0.1 N NaOH until the red color no longer persisted. The organic phase was then separated and concentrated to dryness. The resulting material was purified via MPLC (5:95, MeOH/EtOAc) to provide the title compound, 45I (4.0 g, 9.45 mmol, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H) 7.77 (dd, J=9.73, 1.64 Hz, 1 H) 7.85 (d, J=9.60 Hz, 1 H) 7.97-8.08 (m, 1 H) 8.53 (d, J=9.60 Hz, 1 H) 8.98 (d, J=1.01 Hz, 1 H) 9.02 (s, 1 H). ESI-MS:m/z 423.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=O)[S:9][C:5]=2[CH:4]=1)#[N:2].[ClH:15].Cl.[NH2:17][C@@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:15].[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@@H:18]([NH:17][C:10]([C:8]1[S:9][C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:14]=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:19]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: N#Cc1ccc2cc(C(=O)O)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1

Procedure:
320.8 mg (1.1 mmol) of 6-cyano-1-benzothiophene-2-carboxylic acid (Example 25A), 200 mg (1.0 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 458.3 mg (1.21 mmol) of HATU, 467.3 mg (3.62 mmol) of N,N-diisopropylethylamine and 4.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of methanol and 4 M hydrogen chloride in dioxane and then concentrated and dried under high vacuum. 222.1 mg (64% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[NH:4][N:5]=[C:6]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[OH-].[Na+].CO>O>[Cl:1][C:2]1[C:3](=[O:30])[NH:4][N:5]=[C:6]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COC(=O)CCCCCOc1n[nH]c(=O)c(Cl)c1NCc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2c(OCCCCCC(=O)O)n[nH]c(=O)c2Cl)cc1OC
Reaction time: 1 h

Procedure:
A mixture comprising 240 mg of 4-chloro-5-(3,4-dimethoxybenzylamino)-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 1) prepared in Preparation Example 1, 65 mg of sodium hydroxide, 10 ml of methanol and 1 ml of water, was stirred at 60°-70° C. for 1 hour. After the reaction liquor was evaporated under reduced pressure, water was poured to the residue, and the resultant solution was adjusted to pH 1-2 with dilute hydrochloric acid, whereupon the product was extracted with chlorform. The extract was washed with water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 192 mg of the above identified compound as colorless crystals having a melting point of from 150.5° C. to 151.5° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[C:37]([NH:39][CH:40]3[CH2:42][CH2:41]3)[N:36]=[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH:34]=2)[CH:30]=[N:31][CH:32]=1>COCCOC.C(Cl)Cl>[CH:40]1([NH:39][C:37]2[N:36]=[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH:34]=[C:33]([C:29]3[CH:30]=[N:31][CH:32]=[C:27]([C:14]4[CH:15]=[CH:16][C:11]([CH2:10][N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][CH:13]=4)[CH:28]=3)[CH:38]=2)[CH2:42][CH2:41]1
Reactant: CC(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)N1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)CC1

Procedure:
To a solution of 4-((4-Isopropyl-piperazin-1-yl)methyl)-phenyl boronic acid (Intermediate B3) (3 eq, 0.408 mmol, 0.106 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (6 eq, 0.816 mmol, 0.8 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 50 mg) and PdCl2dppf (0.1 eq, 0.0136 mmol, 10 mg). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 505.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[CH:12][CH:11]=1)([O-])=O>Cl>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccno1
Agent: Cl
Product: Nc1ccccc1-c1ccno1
Temperature: 10 °C
Yield: 67.8 %

Procedure:
To a suspension containing 206 g of stannous chloride dihydrate in 520 ml of concentrated hydrochloric acid was cautiously added 56 g of 5-(2-nitrophenyl)isoxazole, prepared in Example 2. The resulting suspension was refluxed on a steam bath for about 1 hour, then cooled to 10° C. and filtered. The solid was added to about 600 ml of ice-water, and the suspension was made basic to a pH of about 10 with addition of 50% NaOH. The aqueous mixture was extracted with methylene chloride. After drying the methylene chloride extract over sodium sulfate, the solvent was evaporated under reduced pressure to give 32 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH2:22]O)[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][O:4]1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:37][C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1>C1COCC1>[CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][S:37][C:38]3[NH:42][C:41]4[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=4[N:39]=3)[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][O:4]1)[CH3:2]
Reactant: CCC1(CCOc2ccnc(CO)c2C)OCC2(CO1)OCCO2
Reactant: Sc1nc2ccccc2[nH]1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a THF (10 ml) solution of the (4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methanol (560 mg, 1.65 mmol) obtained in the step (4g), triethylamine (0.48 ml, 3.44 mmol) was added at room temperature and thereafter, methanesulfonyl chloride (0.19 ml, 2.45 mmol) was added while cooling in an ice salt bath and stirred under the same conditions for 30 minutes. After the ice salt bath was removed, 2-mercaptobenzimidazole (248 mg, 1.65 mmol) was added and stirred at room temperature for 22 hours. After the reaction mixture was concentrated, NH silica gel was added to the residue and dried. The crude substance was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0, 1/1-0/1 gradient) and a desired fraction(s) was concentrated. The obtained foamy product was dissolved in chloroform and diethyl ether was added thereto. The resulting solid was collected by filtration to obtain the title compound (410 mg, yield: 52.7%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[CH:17]([CH3:19])[CH3:18]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[CH2:16][C:17]([CH3:19])([CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)Cc2ccc(OCc3ccccc3)cc2O1
Yield: 59.8 %

Procedure:
3-Benzyloxyphenol (5.0 g), 2.0 g of isobutyraldehyde, 0.1 g of methanesulfonic acid and 50 ml of toluene were put into a flask equipped with the Dean-Stark condenser, and stirred under reflux for 4 hours. Low-boiling compounds were evaporated under reduced pressure. The residue was purified by column chromatography to give 3.8 g of 6-benzyloxy-2,3-dihydro-2,2-dimethylbenzofuran as a brown liquid. This product was dissolved in ethanol, and 0.4 g of 5% palladium-carbon was added. The mixture was stirred at room temperature for 8 hours in an atmosphere of hydrogen. The catalyst was separated by filtration, and the filtrate was concentrated. The residue was purified by column chromatography to give 2.0 g (yield 50%) of the desired product as a pale yellow liquid.
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:26][C:27]([O-:29])=[O:28])([C:16]2[C:24](O)=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([C:16]3[CH:17]=[C:18]4[O:22][CH2:21][O:20][C:19]4=[CH:23][C:24]=3[O:29][C:27](=[O:28])[CH2:26]2)[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C(CC(=O)[O-])(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN1C(=O)C2(CC(=O)Oc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a solution of 2-(1-hexyl-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-2-oxoindolin-3-yl)acetate (0.19 g, 0.43 mmol) in THF:H2O (2:1) was added lithium hydroxide (0.04 g, 0.86 mmol). The mixture was stirred at ambient temperature for 4 hrs. The organic solvent was removed in vacuo and the pH of the aqueous residue was adjusted to 2 followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography eluting with 25% ethyl acetate/hexane to yield the title compound (0.09 g, 53%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.33 (dt, 1H), 7.14-7.03 (m, 2H), 6.93 (d, 1H), 6.66 (s, 1H), 6.06 (s, 1H), 5.88 (dd, 2H), 3.76-3.63 (m, 2H), 2.94 (q, 2H), 1.69-1.62 (m, 2H) 1.34-1.22 (m, 6H), 0.83 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 175.9, 165.8, 148.3, 147.2, 144.6, 142.6, 129.9, 129.6, 123.8, 123.4, 114.7, 109.2, 105.1, 101.9, 99.8, 49.6, 40.3, 37.2, 31.2, 27.2, 26.4, 22.4, 13.9; MS (ES+) m/z 394.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]1[NH:30][CH:31]=[CH:32][CH:33]=1)=[O:28])=[N+:22]=[N-:23]>>[NH:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:27]([NH:26][CH2:25][CH2:24][N:21]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH2:1])[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=2)[N:23]=[N:22]1)=[O:28]
Reactant: [N-]=[N+]=NCCNC(=O)c1ccc[nH]1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccc[nH]3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.097 g, 0.349 mmol) was reacted with N-(2-azidoethyl)-1H-pyrrole-2-carboxamide (0.063 g, 0.349 mmol) following the general click procedure to give tert-butyl 4-(5-(1-(2-(1H-pyrrole-2-carboxamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-2-amino-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), δ 7.36 (d, 2H), δ 7.24 (s, 1H), δ 6.84 (t, 1H), δ 6.43 (s, 1H), δ 6.04 (s, 2H), 4.49 (s, 2H), δ 3.89 (s, 2H), δ 2.53 (s, 2H), δ 2.09 (s, 2H), δ 1.44 (m, 13H), δ 1.24 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 164.8, 164.6, 161.5, 137.5, 122.3, 111.0, 110.7, 107.5, 107.1, 106.8, 85.1, 49.4, 40.5, 29.3, 28.9, 28.2, 25.5 ppm; HRMS (ESI) calcd for C22H32N8O3 (M+) 456.2597. Found 456.2590, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-1H-pyrrole-2-carboxamide hydrochloride (0.129 g, 94% yield). 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), δ 7.41 (s, 2H), δ 7.17 (s, 1H), δ 6.50 (s, 1H), δ 4.74 (s, 2H), δ 3.98 (s, 2H), δ 2.88 (s, 2H), δ 2.49 (s, 2H), δ 1.78 (m, 4H), δ 1.44 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 166.3, 164.5, 162.0, 161.9, 137.4, 110.6, 110.3, 110.2, 108.5, 17.1, 106.8, 59.3, 52.4, 39.5, 36.5, 27.9, 27.8, 27.6, 24.1, 23.5, 23.3 ppm; HRMS (ESI) calcd for C17H24N8O (M+) 356.2073. Found 356.2080.