Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:24])[NH2:22]>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([NH:34][CH3:35])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[O:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: CNS(=O)(=O)c1ccc(C(=O)NN)cc1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 27.5 %

Procedure:
1-[5-(4-t-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.228 mmol, 62 mg), 4-(hydrazinocarbonyl)-N-methylbenzenesulfonamide (0.228 mmol, 52 mg) and p-tosylic acid monohydrate (30 mol %, 11.8 mg) were dissolved in isopropyl alcohol (6 mL) and stirred at 100° C. for 19 hours. Then, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (30.3 mg, yield 28%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(Cl)nc1
Product: N#Cc1cc(-c2ccc(Cl)nc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (73 mg, 87%), MS (ISP) m/z=337.4 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.O>CN(C=O)C>[C:17]1([CH:16]2[O:23][C:4]3[CH:5]=[N:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]=3[NH:14][CH2:15]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(CNc1c(Br)cnc2ccccc12)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(C2CNc3c(cnc4ccccc34)O2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Sodium hydride (obtained from 2 g of 50% suspension in mineral oil) was added to a solution of 3-bromo-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine (10 g) in 50 ml of DMF and the mixture was stirred at 90° C. for two hours. After cooling to room temperature, it was poured into 250 ml of water and the product extracted with two portions of 100 ml dichloromethane. The dichloromethane layer was dried over sodium sulfate and concentrated. The oily residue was dissolved in 80 ml of isopropanol, the solution was poured into 250 ml of ice water and the mixture was stirred for 1 hour. The solid was filtered and recrystallized from isopropanol. The yield was 3.1 g, mp 194°-195° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
4-Hydroxy-4′-cyanobiphenyl (10.35 g, 53.0 mmol), 6-chloro-1-hexanol (9.05 g, 66.3 mmol), cesium carbonate (18.99 g, 58.3 mmol), and potassium iodide (0.88 g, 5.3 mmol) were dissolved in N,N-dimethylformamide (DMF, 130 mL). The reaction mixture was stirred at 80° C. for 6 h. The resultant salt was removed by hot filtration. The filtrate was slowly added to 600 mL water, and the crude product was collected for recrystallization from methanol to yield 8 (14.24 g, 91.0%). 1H NMR spectral data (400 MHz, CDCl3): δ 1.40-1.70 (m, 6H, CH2—), δ 1.87 (m, 2H, —CH2—), δ 3.69 (t, 2H, —CH2OAr), δ 4.03 (t, 2H, HOCH2—), δ 6.80–7.90 (m, 8H, aromatic rings).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1.[N:14](OCCC(C)C)=[O:15]>C(O)C>[N:14]([C:11]1[CH:10]=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[C:12]=1[NH2:13])=[O:15]
Reactant: Nc1ccnn1-c1ccccn1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1-c1ccccn1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
HCl (37%, 11 μl) was added to a heterogeneous solution of 2-pyridin-2-yl-2H-pyrazol-3-ylamine (2.2 g, 13.7 mmol) in absolute ethanol (15 ml). The reaction mixture was subsequently cooled to 0° C. and isopentyl nitrite (2.02 ml, 15 mmol) was slowly added. The reaction mixture became dark. After the isopentyl nitrite had been completely added, the reaction mixture was allowed to return to ambient temperature. After 2.5 h at ambient temperature, the reaction mixture was cooled to 5° C. and filtered. The solid was washed with absolute MeOH (10 ml) and was then triturated twice from heptane. The solid was dried under vacuum at 35° C. to give 4-nitroso-2-pyridin-2-yl-2H-pyrazol-3-ylamine (2.1 g, 81%) in the form of a green solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([O:15][CH2:14][CH2:13][O:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1Nc2cc(Br)ccc2C12OCCO2
Yield: 85.7 %

Procedure:
Into the solution of 6-bromoindoline-2,3-dione (3.3 g) in Toluene (90 mL), was added Ethylene Glycol (9 g) and p-TsOH (555 mg). The reaction was heated to reflux and water was removed. After completion of the reaction, Toluene was removed, the residue was purified by silica gel column chromatography to provide 3.38 g of 6′-bromospiro[[1,3]dioxolane-2,3′-indolin]-2′-one. 1H NMR (400 MHz, Chloroform-d) δ 7.59 (br., 1H), 7.21 (d, J=1.1 Hz, 2H), 7.00 (s, 1H), 4.60-4.51 (m, 2H), 4.35-4.27 (m, 2H).
Reaction SMILES: CO[C:3](=[O:16])[C:4]([CH2:9][NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH2:7][CH3:8])[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([N+:31]([O-])=O)=[CH:26][N:25]=1>CC(C)=O.C(O)(=O)C.[Fe]>[Cl:23][C:24]1[N:29]=[C:28]2[C:27]([NH:31][C:3](=[O:16])[C:4]([CH2:5][CH3:6])([CH2:7][CH3:8])[CH2:9][N:10]2[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:26][N:25]=1
Reactant: CCC(CC)(CNC1CCCC1)C(=O)OC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
To a solution of methyl2-[(cyclopentylamino)methyl]-2-ethyl-butanoate (Intermediate 252; 7.1 g, 31.3 mmol) in acetone (150 mL) was added potassium carbonate (5.3 g, 38.0 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 6.1 g, 31.3 mmol). The black mixture was stirred at room temperature for 18 hours. The reaction was filtered and the solvent removed in vacuo to yield a black gum, which was dissolved in acetic acid (175 mL) and iron (7.0 g, 125 mmol) added and the reaction heated at 80° C. overnight. The resulting solution was filtered and the solvent removed in vacuo, the black solid/gum was quenched with water (75 mL) and to this was added sodium carbonate until basic, the resultant black emulsion was filtered through a pad of celite. The obtained mixture was extracted with DCM (3×150 mL), dried and the solvent removed in vacuo to yield a black solid. This was passed through a bond elute column (50 g) eluting with 0-1% MeOH in DCM to afford a brown solid, which was triturated with diethyl ether to yield the title compound as a white solid (3.05 g, 30%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:5]1[CH:4]=[CH:3][C:2]([C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccccc1COc1ccc(Br)cc1C(=O)Nc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1COc1ccc(-c2cnn(C)c2)cc1C(=O)Nc1cccnc1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-({[2-(methyloxy)phenyl]methyl}oxy)-N-3-pyridinylbenzamide (may be prepared as described in example 21; 115 mg, 0.28 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (63.7 mg, 0.31 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.56 ml, 0.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (19.29 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 10 mg.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.C1C(=O)N([I:31])C(=O)C1>C(Cl)Cl>[I:31][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To the solution of 1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole (2.3 g, 9.73 mmol) in CH2Cl2 (6 ml) was added TFA (3.0 ml, 38.9 mmol), and NIS (2.41 g, 10.71) at rt. After being stirred at rt for 3 h, the reaction mixture was diluted with CH2Cl2, quenched with NaHCO3 (aq), washed with aq Na2S2O3, water and brine. Dried over Na2SO4, filtered and concentrated to afford 5-iodo-1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole (3.4 g) which was used in the next step without further purification. LCMS: [M+1]+=363.0
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)=[CH:36][CH:37]=1)=[O:1]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(CO)cc2)c2ncnn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C=O)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
A mixture of 4′-({4-[4-hydroxymethylbenzyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.3 g), manganese dioxide (7.0 g) and methylene chloride (15 mL) was stirred at room temperature for 16 hr. The insoluble material was filtered off through celite, and the filtrate was concentrated to give the title compound as a colorless solid (1.3 g, 96%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:18]1([C:15]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][N:8]([CH3:7])[C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:17][CH2:16]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C1CC(=O)O1
Reactant: CNCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Diketene (0.98 mL, 12.7 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-[3-(N-methylamino)propyl]-4,4-diphenylpiperidine (2.61 g, 8.46 mmol, 1.00 equiv) in anhydrous toluene (30 mL) under argon, and stirring was continued for 1 hour. After removal of the solvent, the residue was purified by flash chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0 to 6:1:0.1) to afford 2.97 g (89%) of brown oil, which was characterized spectroscopically.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][NH:20][CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=3[F:38])[CH2:25][CH2:24]2)[CH2:11][CH2:10][CH2:9]1.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42].C(N(CC)CC)C>C(Cl)Cl>[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][N:20]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=3[F:38])[CH2:25][CH2:24]2)[CH2:9][CH2:10][CH2:11]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CNCC4)CC2)c(F)c1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CN(C(=O)N(C)C)CC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (9.1 mg, 0.017 mmol), dimethylcarbamic chloride (3.6 mg, 0.034 mmol) and triethylamine (5.1 mg, 0.050 mmol) in DCM (170 μL) was stirred at room temperature for 30 min. The mixture was purified by HPLC Method A to give the title compound as a TFA salt (6.0 mg, 58.3%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.74-1.84 (m, 2H), 1.89-2.04 (m, 4H), 2.06-2.15 (m, 2H), 2.36-2.46 (m, 2H), 2.79 (t, J=5.7 Hz, 2H), 2.90 (s, 6H), 2.94-3.02 (m, 2H), 3.34-3.43 (m, 2H), 3.51-3.56 (m, 2H), 3.76 (s, 3H), 4.26 (s, 2H), 4.43 (s, 2H), 6.64-6.69 (m, 1H), 6.74 (dd, J=12.9, 3.0 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 499.4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1.[C:30](#[N:32])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[C:30]([C@@H:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)#[N:32]
Reactant: CC#N
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: N#C[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 65 °C
Reaction time: 6.5 h
Yield: 76.2 %

Procedure:
(3S)-1-Benzyl-3-mesyloxypyrrolidine (2.56 g) was dissolved in acetonitrile (3.6 mL). Tetrabutylammonium cyanide (4.95 g) was added to the solution, and the mixture was stirred at 65° C. for 6.5 hours. Saturated sodium hydrogencarbonate (13 mL) and toluene were added dropwise to the reaction mixture, whereby the organic layer was extracted. The organic layer was washed with water and then dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, to thereby give the target compound (1.42 g, yield 76.2%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>COCCOC.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([CH2:12][OH:13])=[CH:10]2
Reactant: OB(O)c1ccccc1
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc2cc(CO)c(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A mixture of (2-chloro-8-methylquinolin-3-yl)methanol (413 mg, 2.0 mmol) and K2CO3 (828 mg, 6.0 mmol) in DME (7.5 mL) and water (7.5 mL) was degassed (×3). Phenylboronic acid (293 mg, 2.4 mmol), PPh3 (21 mg, 0.08 mmol) and Pd(OAc)2 (4.5 mg, 0.02 mmol) were added, the mixture was degassed, then heated at reflux for 75 minutes. The reaction mixture was allowed to cool to r.t. then extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (20 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO2, 10-100% EtOAc in heptane) then by preparative HPLC (Method 1). The product obtained was partitioned between EtOAc and 10% aqueous K2CO3 solution. The organic phase was dried (MgSO4) and evaporated in vacuo to give the title compound (241 mg, 49%) as a white solid. δH (CDCl3) 8.31 (s, 1H), 7.68-7.76 (m, 3H), 7.41-7.59 (m, 5H), 4.86 (d, J 5.1 Hz, 2H), 2.82 (s, 3H), 1.85 (t, J 5.5 Hz, 1H). LCMS (ES+) 250.1 (M+H)+, RT 3.52 minutes (Method 3).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.CC[N:12](C(C)C)C(C)C>>[Br:1][C:2]1[S:3][C:4]([C:7]([NH2:12])=[O:9])=[CH:5][N:6]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Br)s1

Procedure:
Scheme 1 illustrates the synthesis of compounds of Formula 4 and 5. 2-Bromo-thiazol-5-carboxylic acid 1 is reacted with amine 2 in the presence of DMC and DIEA to afford 2-bromo-thiazol-5-carboxamide 3, which without separation is treated with arylboronic acid under Suzuki coupling conditions to give 2-aryl-thiozol-5-carboxamide 4. Reduction of amide 4 with Alane-N,N-dimethylethylamine complex produces compound 5.
Reaction SMILES: [NH2:1][C:2]1[C:20]([NH2:21])=[CH:19][C:5]2[O:6][C:7]([CH3:18])([CH3:17])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.Cl.[C:23](Cl)([Cl:25])=[O:24]>C1(C)C=CC=CC=1>[ClH:25].[OH:16][C@@H:8]1[C:7]([CH3:17])([CH3:18])[O:6][C:5]2=[CH:19][C:20]3[NH:21][C:23](=[O:24])[NH:1][C:2]=3[CH:3]=[C:4]2[C@H:9]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Cl)Cl
Reactant: CC1(C)Oc2cc(N)c(N)cc2[C@@H](N2CCCCC2)[C@@H]1O
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cc3[nH]c(=O)[nH]c3cc2[C@@H](N2CCCCC2)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 6,7-diamino-3,4-dihydro-2,2-dimethyl-trans-4-piperidino-2H-benzo[b]pyran-3-ol (0.12 g) in 5N-hydrochloric acid (10 ml) was treated with a 12.5% solution of phosgene in toluene (20 ml) and the mixture was stirred at room temperature for 45 minutes. A vigorous stream of nitrogen was then passed through the mixture for 10 minutes, and the solution was evaporated to dryness in vacuo. The residue was recrystallised from ethanol-ether to give the hygroscopic 3,6,7,8-tetrahydro-trans-7-hydroxy-6,6-dimethyl-8-piperidino-pyrano[2,3-f]benzimidazole-2 (1H)-one hydrochloride (1) (0.067 g) mp 177°-180° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[C:4]([CH2:19][CH:20]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][N:49]=2)[C:44]([OH:46])=O)[O:21][C:22]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]3=[O:40])[CH2:26][CH2:25]2)=[O:23])[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>C(Cl)Cl>[O:40]=[C:31]1[N:30]([CH:27]2[CH2:26][CH2:25][N:24]([C:22]([O:21][CH:20]([C:41]3[CH:42]=[C:43]([C:44]([N:61]4[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]4)=[O:46])[CH:47]=[CH:48][N:49]=3)[CH2:19][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)=[O:23])[CH2:29][CH2:28]2)[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1
Reactant: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cc(C(=O)O)ccn2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cc(C(=O)N3CCCCC3)ccn2)cc2cn[nH]c12
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of (±)-2-(2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carbonyloxy)ethyl)isonicotinic acid (39.2 mg, 0.057 mmol, 1.0 equiv.) in methylene chloride (0.7 mL) was added a drop of dimethylformamide (catalytic) followed by dropwise addition of oxalyl chloride (2 M in methylene chloride, 0.15 mL, 0.3 mmol, 5 equiv) at room temperature under nitrogen. After 2 h, excess piperidine was added dropwise and the mixture was further stirred for 1 h. The mixture was concentrated to a gel and was suspended in methylene chloride (2 mL). Trifluoroacetic acid (1 mL) was added and the resulting clear tan solution was stirred at room temperature for 6 h. The solvents were removed in vacuo and the residue was partitioned between 1 N sodium hydroxide and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. Purification by flash column chromatography (6% methanol/methylene chloride) afforded the desired product (30.4 mg, 85.4%) as an off-white powder. MS (ESI) [M+H]+=622. 1H-NMR (400 MHz, CDCl3) δ 8.69 (d, J=4.4 Hz, 1H), 7.95 (br., 1H), 7.70 (br., 1H), 7.50-6.80 (m, 6H), 6.68 (br., 1H), 6.05-5.94 (m, 1H), 4.65-3.80 (m, 4H), 3.64 (br., 2H), 3.50-3.18 (m, 2H), 3.18-2.60 (m, 4H), 2.48 (s, 3H), 1.85-1.44 (m, 9H), 1.44-1.10 (m, 4H). HPLC tR=1.79 min.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15].[CH3:19]I.O>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]([CH3:19])[C:12](=[O:18])[CH2:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: Cc1cccc(NC(=O)CC(C)(C)C)c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(N(C)C(=O)CC(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a slurry of NaH in THF at 0° C. was added a solution of N-(2-bromo-3-methylphenyl)-3,3-dimethylbutanamide (1.42 g, 5.00 mmol) in THF. After 20 min at 0° C., methyl iodide (342 μL, 5.50 mmol) was added and the reaction mixture was allowed to stir at RT for 1 h. Additional 200 mg NaH and 0.34 ml MeI were added and the reaction was allowed to stir for 5 min. Water and EtOAc were added to the mixture, and the organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash column chromatography (0-20% EtOAc/hexanes). N-(2-bromo-3-methylphenyl)-N,3,3-trimethylbutanamide was isolated as a clear, colorless oil.