Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[NH2:19][CH2:20][CH2:21][OH:22]>>[C:13]1([CH:2]([NH:19][CH2:20][CH2:21][OH:22])[C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(C(Cl)c2ccccc2)c1
Reactant: NCCO
Product: OCCNC(c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 70 parts of 1-(chlorophenylmethyl)-3-(trifluoromethyl)benzene and 250 parts of 2-aminoethanol is stirred for 3 hours at 140° C. The reaction mixture is cooled and poured onto water. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 60 parts (82%) of 2-[{phenyl[3-(trifluoromethyl)phenyl]methyl}amino]ethanol as a residue.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1/[CH:7]=[C:8]1\[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:16]=2[C:17]\1=[O:18]>CO.C(Cl)(Cl)Cl.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[C:17](=[O:18])[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1[nH]cnc1/C=C1\CCc2cccnc2C1=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1[nH]cnc1CC1CCc2cccnc2C1=O
Reaction time: 1 h
Yield: 5920.8 %

Procedure:
A mixture of (4) (1.39 g, 5.81 mmol) and Pd/BaSO4 (5 wt %, 0.47 g) in methanol and chloroform was hydrogenated at 50 psi for one hour. The reaction mixture was filtered through a bed of Celite, and washed with methanol. The solvents were removed under vacuum. The crude product was purified by chromatography on silica gel with 2 to 3% ammonia saturated methanol in dichloromethane to give 7-((5-Methyl-1H-imidazol-4-yl)methyl)-6,7-dihydroquinolin-8(5H)-one (5) as a yellow oil (0.830 g, 344 mmol, 59% yield).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH2:11]([O:13][C:14]1[CH:29]=[CH:28][C:17]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:26]#[CH:27])[CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[CH3:12].CON(C)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:34]1([C:33](=[O:40])[C:27]#[C:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:18][C:17]3[CH:28]=[CH:29][C:14]([O:13][CH2:11][CH3:12])=[CH:15][CH:16]=3)[CH:21]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: C#Cc1cccc(OCc2ccc(OCC)cc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOc1ccc(COc2cccc(C#CC(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Place lithium hexamethyldisilazane (2 mL of a 1M solution in tetrahydrofuran, 2 mmol) and tetrahydrofuran (8 mL) under an argon atmosphere and cool to 0° C. Add a solution of 3-(4-ethoxybenzyloxy)phenylacetylene (0.51 g, 2 mmol) in tetrahydrofuran and stir the solution for 45 minutes at 0° C. Add N-methoxy-N-methylbenzamide (0.4 g, 2.4 mmol), remove the cooling bath and stir at room temperature for 1 hour. Partition the mixture between ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Filter through silica gel and elute with 10% ethyl acetate/hexane to yield a crude solid. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[NH:12][C:11]3=[O:19])=[CH:4][C:3]=2[O:2]1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH3:26]>CC(C)=O>[CH2:23]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[C:11]1=[O:19])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: O=c1[nH]c2cccnc2n1-c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCn1c(=O)n(-c2ccc3c(c2)OCO3)c2ncccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 2.6 g. (0.01 mole) of 1,3-dihydro-3-(3,4-methylenedioxyphenyl)imidazo[4,5-b]-pyridin-2-one in 150 ml. of acetone, was added 1.12 g. (0.02 mole) of powdered potassium hydroxide. The mixture was stirred at room temperature for 20 minutes and 2.74 g. (0.02 mole) of 1-bromobutane was added. The mixture was stirred at reflux for 16 hours and then evaporated in vacuo. The residue was extracted with a solution of 20 ml. of 2.5 N sodium hydroxide and 50 ml. of water. The product was separated by filtration and was purified by crystallization from ether-petroleum ether giving 2.4 g. of white needles melting at 74°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:15][C:16](=[O:40])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH2:30][NH:31]C(OC(C)(C)C)=O)=[O:24])=[C:19]([Cl:39])[CH:18]=3)[CH2:10][CH2:11][S:12]([CH3:14])=[O:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:15][C:16](=[O:40])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH2:30][NH2:31])=[O:24])=[C:19]([Cl:39])[CH:18]=3)[CH2:10][CH2:11][S:12]([CH3:14])=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfinylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C24H27Cl2N5O3S (536.48); mass spectrum: (M+H)+=536/538/540 (chlorine isotope).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:13][CH:14](O)[C:15]#[CH:16].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[I:13][CH:14]([O:11][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]#[CH:16]
Reactant: C#CC(O)I
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CC(I)OC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a magnetically stirred solution of N-t-butoxycarbonylglycine (3.00 g., 17.12 mmole) and iodopropargyl alcohol (3.12 g., 17.15 mmole) in anhydrous dichloromethane (40 ml.) cooled to 0° C. with an ice-bath was added 4-dimethylaminopyridine (0.21 g., 1.72 mmole) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.61 g., 18.83 mmole). After stirring at 0° C. for 1/2 hour, the reaction mixture was stored in a refrigerator at 6° C. overnight. The reaction mixture was transferred to a separatory funnel and diluted to 100 ml. with dichloromethane, then washed successively with water, 10% aqueous potassium hydrogen sulfate, water, saturated aqueous sodium bicarbonate, water and a final wash with saturated aqueous sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo with a rotary evaporator to a clear colorless oil which crystallized on standing as N-t-butoxycarbonylglycine iodopropargyl ester (5.60 g., 96.4% yield). m.p.=65°-68° C. 1H-NMR (200 MHz, DMSOd6)δ=1.40 ppm, s, 9H; 3.73, d, 2H; 4.86, s, 2H; 7.28, t, 1H. IR (CDCl3) 1165, 1505, 1715, 1760, 2205, 3460 cm-1.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH2:22][N:23]([CH3:25])[CH3:24])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CC(O)=O>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH2:22][N:23]([CH3:25])[CH3:24])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(CN(C)C)cc2ccccc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-((dimethylamino)methyl)naphthalen-2-yl)acetate in THF (0.5 mL) and MeOH (0.5 mL), was added NaOH solution (2N, 100 μL). The reaction mixture was stirred at room temperature for 1 day. The reaction mixture was neutralized by HOAc and concentrated down. The residue was dissolved in MeOH and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to provide the desired product (3.7 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 8.12 (s, 1H), 8.00 (d, J=4.2 Hz, 1H), 7.65-7.52 (m, 5H), 7.32-7.30 (m, 2H), 5.36 (s, 1H), 4.93 (d, J=6.8 Hz, 1H), 4.47 (d, J=7 Hz, 1H), 3.12 (s, 3H), 2.89 (s, 3H), 1.12 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H29C1NO3: 426.2. Found: 426.1, 428.1.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[S:20](Cl)([C:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:28]([N:29]([CH3:31])[CH3:30])[C:27]=2[CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21].Cl>[OH-].[Na+].O1CCCC1>[CH3:30][N:29]([CH3:31])[C:28]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:27]=1[CH:26]=[CH:25][CH:24]=[C:23]2[S:20]([NH:16][CH:15]([CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[C:17]([OH:19])=[O:18])(=[O:22])=[O:21]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)c1cccc2c(S(=O)(=O)NC(CCCNC(=O)OCc3ccccc3)C(=O)O)cccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Nδ -Carbobenzyloxy-L-ornithine (39.6 g, 0.149 mol) was dissolved in a solution of 2N NaOH (90 mL) and tetrahydrofuran (200 mL) under nitrogen. After about 15 minutes at ambient temperature, the mixture was cooled to about 0° C. and subsequently treated with additional 2N NaOH (85 mL) and dansyl chloride (45.0 g, 0.167 mol) in 5 g portions over 15 minutes. The mixture was stirred at about 0° C. for about 1 hour and at room temperature for about 2 hours before it was neutralized to pH 7 with 1N HCl. The precipitate was suction-filtered and the filtrate was diluted with ethyl acetate. The organic phase was then separated, washed with brine, dried over Na2SO4 and concentrated to give a combined yield of 103.17 g (70.4%, two runs) of 2d as a yellow foam which was used directly.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: ClCc1ccc2ccccc2n1
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2Cc2ccc3ccccc3n2)cc1

Procedure:
5,6-dichloro-2-(4-formylphenyl)-1-(quinolin-2-ylmethyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and 2-chloromethylquinoline by following General Procedure 3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH:13]2[CH2:15][CH2:14]2)O)=[CH:5][CH:4]=1)#[N:2].[Br-:16].[Li+].N1C(C)=CC(C)=CC=1C.O>CCOCC>[Br:16][CH2:15][CH2:14][CH:13]=[CH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: [Br-]
Reactant: N#Cc1ccc(CCC(O)C2CC2)cc1
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: N#Cc1ccc(CCC=CCCBr)cc1
Temperature: -60 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
to a solution of 9.8 g of 4-cyanophenylethyl cyclopropyl carbinol in 140 ml of ether was added 4.24 g of lithium bromide and 3 ml of 2,4,6-collidine. The mixture was cooled to -60° C. and 9.8 g of phosphrous tribromide was added over a five minute period. The reaction mixture was allowed to warm to 0° C., kept at that temperature for two hours and then allowed to warm to 18° C. Collidine (18 ml) was added, and after 15 minutes of stirring, the mixture was poured into 200 ml of water and 100 ml of ether. The ether extracts were washed with dilute aqueous sulfuric acid and water, dried over anhydrous magnesium sulfate and concentrated to a volume of 150 ml. Zinc bromide (11.6 g) was then added with cooling, and the mixture was stirred at room temperature for 29 hours. The ether solution was washed with water, dried and concentrated to give 12.5 g of 4-(6-bromohex-3-enyl)benzonitrile as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[N:23]=[C:22](OC)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1>>[CH3:12][O:13][C:14]1[N:23]=[C:22]([NH:11][CH2:1][C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1
Reactant: COc1ccc2nc(OC)nc(OC)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Product: COc1ccc2nc(OC)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 155 °C
Reaction time: 1 h
Yield: 17.8 %

Procedure:
3.75 g (24.8 mmol) of piperonylamine was added to a solution of 2.00 g (8.26 mmol) of the 2,4,6-trimethoxyquinazoline prepared in Example 88 in dimethyl sulfox (15 ml). The obtained mixture was stirred under heating at 150 to 160° C. After one hour, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 0.50 g of the title compounds as a pale-yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH:5]1[C:9]2=[C:10]([S:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:11]3[C:12]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[Cl:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH:5]1[C:9]2=[C:10]([S:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:11]3[C:12]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:13][C:14]([C:42]4[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=4)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(-c3ccc(Cl)cc3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To the compound of Step 2 (53 mg, 0.089 mmol) in toluene/EtOH 3:1 mixture (4 mL) was added 4-chlorophenylboronic acid (28 mg, 0.18 mmol), K2CO3 (18 mg, 0.13 mmol), and tetrakis (triphenylphosphine) palladium (0) (5.1 mg, 0.04 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to provide the title compound (40 mg)
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]([N+:19]([O-])=O)[CH:15]=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCO>[NH2:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH:10]=[N:11]2
Reactant: CC(C)(C)[Si](C)(C)Oc1cnc2cccc([N+](=O)[O-])c2c1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1cnc2cccc(N)c2c1
Reaction time: 1 h

Procedure:
3-(tert-Butyldimethylsilyloxy)-5-nitroquinoline, as described above in Step E, (4.58 g, 15.04 mmol) was dissolved in EtOH (150 mL) and EtOAc (150 mL), the vessel was degassed, Pd/C (0.458 g, 10 wt %) was added and the mixture was subjected to H2 (1 atm) with vigorous stirring for 1 hour. The mixture was filtered through a celite pad and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of 0% to 10% EtOAc in CH2Cl2, to yield the above-titled compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:32])[C:30]#[CH:31]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#CCO
Product: Cc1ccc(-n2cc(CO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.125 mmol) and prop-2-yn-1-ol (0.125 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 60:40 as the eluent to afford the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[N:19]([CH3:26])[N+:18]=3[O-:27])[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[N:19]([CH3:26])[N+:18]=3[O-:27])[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c2c(c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)[n+]1[O-])CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c2c(c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)[n+]1[O-])CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88167.1 %

Procedure:
To a pale yellow solution of 3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (43 mg, 86.2 μmol) in dichloromethane (2.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol51), the reaction mixture turned dark red and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (added few drops MeOH and heating) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. Pure white solid product was sonicated with hexanes. The solid was separated by decantation and dried under high vacuum to give 3-(7-(tert-butylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (28 mg, 76.0 mmol, 88.1%) as a white solid. MS (M+H)+=369.1 (100% purity); 1H NMR (DMSO-d6) δ: 12.88 (br. s., 1H), 8.87 (s, 1H), 8.40 (s, 1H), 7.32 (s, 1H), 3.35 (s, 3H), 2.36-2.46 (m, 2H), 2.03 (br. s., 2H), 1.86-1.96 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8]C)C(O)=O.[C:10](Cl)(=O)[C:11]([Cl:13])=[O:12]>CN(C)C=O>[Br:1][CH2:2][CH2:6][CH2:7][CH2:8][CH2:10][C:11]([Cl:13])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCC(Br)C(=O)O
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCBr

Procedure:
58.5 g of (0.3 moles) of 6 bromohexanoic acid and 85 ml of oxalyl chloride are placed in a 250-ml flask with a magnetic agitator. The mixture is agitated and 1 milliliter of dimethylformamide (DMF) is added.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 72 %

Procedure:
As described for Example 46, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (97 mg, 0.4 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (105 mg, 72%) which was obtained as a light yellow solid. MS: m/e=365.1 [M+H]+.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:15])[CH2:12][O:13][CH3:14])=[CH:9][N:10]=1.Cl.C(=O)([O-])O.[Na+]>CC(C)=O>[OH:15][CH:11]([C:8]1[S:7][C:6]([CH:2]=[O:1])=[N:10][CH:9]=1)[CH2:12][O:13][CH3:14]
Reactant: COCC(O)c1cnc(C2OCCO2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COCC(O)c1cnc(C=O)s1
Yield: 69.8 %

Procedure:
A mixture of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]-2-methoxyethanol (1.84 g), 1M hydrochloric acid (8 mL) and acetone (20 mL) was stirred with heating under reflux for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.04 g, yield 70%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 188 (MH+).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH2:14].[Br:15][C:16]1[C:21]([CH2:22][CH3:23])=[C:20](Br)[N:19]=[CH:18][N:17]=1>CC(N(C)C)=O.C(N(C(C)C)CC)(C)C>[Br:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)[C:21]=1[CH2:22][CH3:23]
Reactant: NCCCc1ccc2c(n1)NCCC2
Reactant: CCc1c(Br)ncnc1Br
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(Br)ncnc1NCCCc1ccc2c(n1)NCCC2
Reaction time: 6 h

Procedure:
A mixture of 0.20 g (1 mmole) of 3-(5,6,7,8-tetrahydro-[1.8]-naphthyridin-2-ylpropylamine [prepared according to J. Org. Chem. 2004, 69, (1959-1966) ] and 0.30 g (1.1 mmoles) of 4,6-dibromo-5-ethyl-pyrimidine in 20 ml of dimethylacetamide and 1 ml of diisopropylethylamine is taken to 120° C. for 6 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silica gel eluting with a gradient of 100% heptane to 100% ethyl acetate. 0.21 g of expected product is obtained in the form of a yellow oil.