Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:11]([OH:23])[C:10]([C:24](=[N:26][NH:27][C:28]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[O:29])[CH3:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:20])[CH3:21])=[CH:17][CH:18]=2)=[C:11]([OH:23])[C:10]([C:24](=[N:26][NH:27][C:28]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[O:29])[CH3:25])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(Cc3ccccc3)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
To methyl 4-[(2-{1-[1-benzyl-5-(4-t-butylphenyl)-4-hydroxy-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.045 mmol, 23.5 mg), methanol was added, and 1 M aqueous sodium hydroxide (0.224 mmol, 0.224 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to 0° C., and 1 M hydrochloric acid (0.224 mmol, 0.224 mL) and water were added. The precipitated solid was recovered by filtration, washed with water, dried by means of a vacuum pump and purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (15.8 mg, yield 69%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[CH:3]=1.C([Li])CCC.CN(C)[CH:17]=[O:18]>CCOCC.C(OCC)(=O)C>[I:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([I:8])[CH:5]=1)[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Ic1cc(I)cc(I)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=Cc1cc(I)cc(I)c1
Reaction time: 0.25 h

Procedure:
To a slurry of 1,3,5-triiodobenzene (7.5 G, 16.4 mM) in 72 mL of ether at -78° was added n-butyllithium 7.2 mL; 18 mM). After 15 minutes of stirring, 2.8 mL (36 mM) of N,N-dimethylformamide was added dropwise and the reaction mixture was stirred overnight. After diluting with 100 mL of ethyl acetate, the reaction mixture was washed with 3×50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Solvent removal gave a crude product, which was chromatographed on silica gel (application in minimum amount of CH2Cl2 ; and elution with 1:9 EtOAc:hexane) to yield 1.3 G of the desired aldehyde as cream colored solid.
Reaction SMILES: C([Li])CCC.[C:6]1([CH:12]([CH3:28])[CH2:13][C:14]2([CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])(=O)=O.O>CCCCCC.O1CCCC1.O1CCCC1.CCCCCC>[CH3:36][N:35]([CH2:34][CH2:33][C:15]1[C:14]([CH2:19][CH:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])([CH2:13][CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:28])[CH:18]=[CH:17][CH:16]=1)[CH3:37]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Reactant: CC(CC1(CC(C)c2ccccc2)C=CC=C1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(CC1(CC(C)c2ccccc2)C=CC=C1CCN(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
12.5 mL of a 1.6 molar solution of n-butyllithium in hexane was added dropwise to a cooled (0° C.) solution of di-(2-phenyl-propyl)-cyclopentadiene (6.05 g; 20.0 mmol) in dry tetrahydrofuran (100 ml) under a nitrogen atmosphere in a 250 mL three-necked round-bottomed flask provided with a magnetic stirrer and a dropping funnel. After 24 hours of stirring at room temperature, a solution of 2-dimethylaminoethyl tosylate (20.0 mmol) prepared in situ in tetrahydrofuran/hexane was added. After 18 hours of stirring, the conversion was found to be 90%, and water (100 ml) was carefully added dropwise to the reaction mixture and the tetrahydrofuran was then distilled off. The crude product was extracted with ether, and the combined organic phase was then dried with sodium sulphate, and boiled down. The residue was purified on a silica gel column, which resulted in 5.98 grams (80%) of (dimethyl-aminoethyl)di(2-phenyl-propyl)cyclopentadiene.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:7])[CH2:2]1.ClC1C=CC=C(C(OO)=[O:35])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:35]=[S:1]1[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[O:7])[CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCSC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCS(=O)C1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of benzyl 2(S)-(3-thiazolidine-carbonyloxy)-3-phenylpropionate (371 mg) in methylene chloride (7 ml), which was cooled to 0° C., was added 80% m-chloroperbenzoic acid (215 mg). The mixture was stirred at same temperature for 30 minutes. Then 10% sodium sulfite aqueous solution and methylene chloride were added thereto, and the mixture was separated. The separated aqueous layer was extracted with methylene chloride (2 times). The combined extract was washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure. Obtained crystals were washed with n-hexane to give benzyl 2(S)-(1-oxo-thiazolidine-3-carbonyloxy)-3-phenylpropionate (350 mg).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][C@@H:11]3[CH2:13][C@H:8]2[CH2:9]N3C(OC(C)(C)C)=O)=[CH:4][CH:3]=1>C(Cl)Cl>[N:7]1([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:22][CH:21]=2)[CH2:12][CH2:11][CH2:13][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(O)cc1
Solvent: ClCCl
Product: Oc1ccc(CN2CCCCC2)cc1

Procedure:
The title compound was prepared using methods analogous to those described for Intermediate 35, substituting DCE for CH2Cl2. 1H NMR (500 MHz, CDCl3): 7.14-7.03 (m, 2H), 6.75 (br s, 1H), 6.62-6.53 (m, 2H), 3.41 (s, 2H), 2.49 (s, 4H), 1.66-1.59 (m, 4H), 1.50-1.42 (m, 2H). MS (ESI): mass calcd. for C12H17NO, 191.13; m/z found, 192.20 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH2:11]([Mg]Br)[CH3:12].CO.[H-].[H-].[H-].[H-].[Li+].[Al+3]>[Cu]Br.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([NH2:7])[CH2:11][CH3:12])[CH:8]=[CH:9][CH:10]=1
Reactant: CC[Mg]Br
Reactant: COc1cccc(C#N)c1
Agent: [Cu]Br
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(N)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A flame-dried 250 mL R.B. flask equipped with a reflux condenser was charged, under argon, with 3-methoxybenzonitrile (2 g, 15 mmol) and dry THF (33.5 mL). Ethylmagnesium bromide (1 M) in THF (16.5 mL, 16.5 mmol) was then added followed by copper (I) bromide (43 mg, 0.3 mmol). The reaction mixture was refluxed for 30 min and then cool down to 0° C. before MeOH (0.61 mL, 15 mmol) was added. The reaction mixture was stirred for 10 min before LAH (1M) in THF (30 mL, 30 mmol) was added and stirred for 60 min at room temp. The reaction was quenched with an aqueous 2M solution of Rochelles' salts (200 mL), stirred for 60 min at room temperature, extracted with diethyl ether (4×30 mL), the organic extracts dried, filtered and concentrated to give the product (2.37 g, 96%) which was sufficiently pure for the next step. 1H NMR (400 MHz, methanol-d4) δ: 0.85 (t, 3H, J=7.4 Hz), 1.68-1.77 (m, 2H), 3.70 (dd, 1H, J=6.6 Hz), 3.81 (s, 3H), 6.81 (d, 1H, J=8.2 Hz), 6.90 (d, 1H, J=8.0 Hz), 6.91 (s, 1H), 7.24 (t, 1H, J=7.8 Hz).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C@@H:13]2C[C@H:14]2C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:7]1([C@@H:13]2[CH2:14][C@H:1]2[C:2]([Cl:4])=[O:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reaction time: 2 h

Procedure:
In a dry 250 ml round-bottomed flask was added oxalyl chloride (0.90 ml, 1.8 mmol) to 8A (0.60 g, 3.5 mmol) in CH2Cl2 at room temperature to give a yellow solution. In 2 hours, the reaction was complete. The crude mixture was concentrated in vacuo and residual TFA was removed azeotropically with toluene 3 times to give the desired product (1R,2R)-2-phenylcyclopropanecarbonyl chloride (8A-1), which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.O.[OH-].[Cs+].Br[CH2:34][CH3:35].[ClH:36]>CN(C)C=O>[ClH:36].[ClH:36].[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:4]2[CH:5]=[N:1][N:2]([CH2:34][CH3:35])[CH:3]=2)[N:8]=1)[CH3:29]
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CCBr
Agent: Cl
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2cnn(CC)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol; prepared according to Example 21, Step A) in dry N,N-dimethyl formamide (0.5 mL) was added cesium hydroxide hydrate (8.7 mg, 0.052 mmol) and bromoethane (5.7 mg, 0.052 mmol). The mixture was stirred under a nitrogen atmosphere for 60 minutes at ambient temperature. The mixture was filtered, washed with methanol and ethyl acetate, and concentrated under a stream of nitrogen. The material was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The isolated product was dissolved in a mixture of dichloromethane and methanol. Hydrogen chloride (0.5 mmol; 2M solution in diethyl ether) was added. Removal of the solvent under reduced pressure followed by high vacuum gave N-(3-ethyl-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (5.0 mg). MS (APCI), positive scan, m/z=414.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1>CO.[Pt]>[Br:1][C:2]1[C:10]2[C:9]([C:11]3[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=3)[NH2:17])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(-c2ncnc3[nH]cc(Br)c23)c1
Agent: [Pt]
Solvent: CO
Product: Nc1cccc(-c2ncnc3[nH]cc(Br)c23)c1
Reaction time: 8 h

Procedure:
To 5-bromo-4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (9.5 g, 30 mmol) in methanol (99 mL) was added 3% Pt on carbon doped with 0.6% V (4.84 g, 0.744 mmol) and the mixture was stirred under H2 balloon overnight. The mixture was filtered over Celite and the filtrate washed with DCM/MeOH. The reaction solution was then concentrated under reduced pressure to afford 3-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline. LRMS (ESI) calc'd for C12H10BrN4[M+H]+: 289, found 289.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.O.ClCCl.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][NH:20][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: O
Product: CC(C)CNc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine (548 mg, 3 mmol) in isobutylamine (1.5 mL) was stirred at room temperature for 17 hours. To the mixture was added water (5 mL) and dichloromethane (5 mL). The organic layer was separated and purified by flash silica (Si) chromatography (0-100% dichloromethane-cyclohexane gradient) to give the title compound (455 mg) as a colourless oil. LCMS (2 min, formic) Rt 1.20 min, m/z (ES+) 220 (M+H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[O:18]1[CH2:20][CH:19]1[CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:20][CH:19]([OH:18])[CH2:21][CH2:22][NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: c1ccc(NCCC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(CCNc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
NaH (60% dispersed in mineral oil, 0.0018 g, 0.0452 mmol) was added to a solution of 3,6-dibromocarbazole (0.0147 g, 0.0452 mmol) in 0.5 mL anhydrous THF and the mixture was stirred for 15 min. N-(2-(oxiran-2-yl)ethyl)aniline (0.0067 g, 0.0410 mmol) in 1.5 mL anhydrous THF solution was added dropwise and the resulting mixture was stirred at 60° C. overnight. THF was removed under vacuum and the residue was dissolved in 10 mL EtOAc and washed with water 2×5 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.0115 g colorless oil; yield 57.5%.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[NH4+:24].Cl>ClCCl>[NH2:24][CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of alcohol 20 (500 mg, 2.1 mmol) in dichloromethane at room temperature was added thionyl chloride (0.25 mL, 3.14 mmol) and the resulting reaction mixture is allowed to stir at room temperature for half hour. Thereafter concentrated ammonium hydroxide (10 mL) was added and the resulting reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was poured onto 1N HCl and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography (SiO2, 35% EtOAc-Hexanes eluant) provided 310 mg of 24 as a white solid (500 mg theoretical, 62% yield).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1.Cl>C(O)C>[OH:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(Cc2ccc(OC)cc2)cn1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(Cc2ccc(O)cc2)cn1
Temperature: 120 °C
Yield: 84.4 %

Procedure:
One gram of ethyl 5-(4-methoxybenzyl)picolinate was dissolved in 20 ml. of ethyl alcohol saturated with hydrochloric acid. The solution was heated in a sealed tube at 120° C. for 24 hours. The solvent was distilled out and the residue was added with cold water. Crystals thus formed were collected by filtration and recrystallized from ethyl acetate to obtain 0.8 g of ethyl 5-(4-hydroxybenzyl)-picolinate as colorless needle-like crystals of a melting point of 153°~156° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][O:18][CH3:19])[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4].C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1([CH2:17][O:18][CH3:19])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COCC1(C(=O)OC)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COCC1(C(=O)OC)CCNC1
Yield: 56.9 %

Procedure:
A mixture of 1-benzyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (373 mg, 1.42 mmol), ammonium formate (358 mg, 5.68 mmol), 10% Pd/C (100 mg) and methanol (6 ml) was refluxed overnight. The mixture was filtered through Celite, washed with ethyl acetate. The combined filtrate was concentrated and the residue was taken into ethyl acetate, washed with small amount of water. Aqueous layer was isolated, extracted with dichloromethane three times. The dichloromethane extracts were combined with previous ethyl acetate extracts and dried over MgSO4. Evaporation of solvents provided the title compound as oil (140 mg, 57%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:17])([CH3:16])[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-])=O.C([O-])(=O)C.[Na+].CO>[Cl-].[Cl-].[Cl-].[Ti+3].O>[Cl:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:13][C:3](=[O:2])[C:4]([CH3:17])([CH3:16])[NH:5]2
Reactant: COC(=O)C(C)(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC1(C)Nc2cc(Cl)ccc2NC1=O
Reaction time: 2.5 h

Procedure:
Aqueous titanium trichloride (20%, 260 ml) is added dropwise over 10 min to a mixture of N-(5-chloro-2-nitrophenyl)-2-methylalanine methyl ester, (XI, EXAMPLE 11, 14.1 g), sodium acetate (240 g), methanol (504 ml) and water (156 ml). The mixture is stirred for 2.5 hr at 20°-25°. The material is partitioned between aqueous sodium bicarbonate and ethyl acetate, the phases are separated, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure with heat to give the title compound, mp 166°-170°; IR (mineral oil) 3311, 2964, 2954, 2925, 1658, 1614, 1505, 1404 and 1355 cm-1 ; NMR (CDCl3) 8.67, 6.73, 6.6-6.7, 3.78 and 1.42 δ; MS (FAB) m/z 210, 195 and 167.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:44]([N+:48]1[N:52]=[C:51]([CH3:53])[S:50][C:49]=1[CH3:54])[CH2:45][CH2:46][CH3:47]>>[CH2:44]([N:48]1[N:52]=[C:51]([CH3:53])[S:50]/[C:49]/1=[CH:54]\[C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:9])[CH2:45][CH2:46][CH3:47]
Reactant: O=C(O)C1CCCCC1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial cyclohexanecarboxylic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.92 (m, 3 H) 1.10-1.39 (m, 8 H) 1.58-1.76 (m, 8 H) 2.23-2.31 (m, 1 H) 2.38-2.41 (s, 3 H) 4.04 (t, 2 H) 5.90 (s, 1 H); MS (ESI) m/z 281 (M+H)+.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][C:18](=[O:23])[C:19]#[C:20][CH2:21][CH3:22])[CH3:16]>CN(C)C=O>[CH2:15]([O:17][C:18]([C:19]1[C:20]([CH2:21][CH3:22])=[N:2][N:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=12)=[O:23])[CH3:16]
Reactant: CCC#CC(=O)OCC
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)nn2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
To a solution of amino-pyridinium iodide (22 g, 99 mmol) and anhydrous potassium carbonate (17.8 g, 128.7 mmol) in dimethylformamide (225 mL) was added ethyl-2-pentynoate (24.98 g, 198 mmol). The solution was stirred at room temperature for 24 h. The reaction mixture was poured into 1.2 L of ice water. The resulting light brown precipitate was collected by vacuum filtration and air-dried for 16 h to yield crude product (11.9 g, 55%), which was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>O1CCCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([OH:19])[CH2:14][CH2:15][N:16]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Methanesulfonyl chloride (21.91 g, 14.81 mL, 191.30 mmol) is added slowly (10 min) to a solution of 4-(4-bromophenyl)-4-piperidinol (50.00 g, 191.30 mmol) and triethylamine (29.04 g, 40.00 mL, 286.95 mmol) in tetrahydrofuran (575 mL) at 23° C. (internal temperature) under nitrogen atmosphere. The mixture is stirred at 23° C. for 30 min. 500 mL of 1 M aq hydrochloric acid are added and the mixture is stirred for 10 min. The mixture is extracted with ethyl acetate (2×500 mL) the organic layers are combined, dried over anhydrous sodium sulfate, filtered and the solvent is removed to obtain 60.0 g of the title compound as a white solid. MS m/e (79Br/81Br) 333, 335 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]([CH3:16])=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:17]([O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Cl.CCOCC>O1CCOCC1.CO.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH:13]([N:12]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:29]3[CH:28]=[CH:27][C:26]([S:23](=[O:24])(=[O:25])[NH:22][CH2:21][CH2:20][O:19][CH2:17][CH3:18])=[CH:31][CH:30]=3)[N:7]=2)=[CH:9][N:10]=[C:11]1[CH3:16])([CH3:14])[CH3:15]
Reactant: CCOCCNS(=O)(=O)c1ccc(I)cc1
Reactant: Cc1ncc(-c2ccnc(N)n2)n1C(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3C(C)C)n2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 2-amino-4-(1-isopropyl-2-methylimidazol-5-yl)pyrimidine (Method 39; 163 mg, 0.75 mmol), N-(2-ethoxyethyl)-4-iodobenzenesulphonamide (Method 44; 400 mg, 1.13 mmol), tris(dibenzylideneacetone) dipalladium (0) (35 mg, 0.038 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (47 mg, 0.076 mmol) in dioxane (10 ml) was added sodium t-butoxide (258 mg, 2.69 mmol) and the mixture heated at 80° C. overnight. The reaction was cooled to room temperature and MeOH 105 ml) was added and the mixture poured onto an Isolute SCX-2 column, eluted first with MeOH (10×30 ml) and the product was then eluted with 5% methanolic ammonia (10×30 ml). The solvent was removed by evaporation and the residue purified by flash chromatography on silica gel eluting with DCM/MeOH (100:0 increasing in polarity to 97:3) to yield a foam which was dissolved in MeOH (2 ml) and treated with 1N HCl in ether (350 μl, 0.35 mmol) for 5 minutes. Solvent was evaporated in vacuo to yield a yellow foam which was triturated with ether to yield after filtration the title compound as a yellow solid (141 mg, 39%) NMR: 1.05 (t, 3H), 1.53 (d, 6H), 2.80 (s, 3H), 2.85 (q, 2H), 3.32 (m, 4H), 5.58 (m, 1H),7.21 (d, 1H), 7.52 (t, 1H), 7.73 (d, 2H), 7.86 (d, 2H), 8.39 (s, 1H), 8.68 (d, 1H), 10.18 (brs, 1H); m/z 445.