Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.[CH3:20][C:21]1[C:22](=[O:50])[N:23]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:24](=[O:37])[C:25]=1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>O1CCCC1.C(OCC)(=O)C>[C:42]([C:41]1[CH:44]=[CH:45][C:38]([N:23]2[C:22](=[O:50])[C:21]([CH3:20])=[C:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][N:34]([C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([N:9]([CH3:19])[CH3:8])=[CH:11][CH:12]=4)=[O:18])[CH2:33][CH2:32]3)[C:24]2=[O:37])=[CH:39][C:40]=1[C:46]([F:47])([F:49])[F:48])#[N:43]
Reactant: CC1=C(CCCCCN2CCNCC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(CCCCCN2CCN(C(=O)Nc3ccc(N(C)C)cc3)CC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.2 ml of a solution of triethylamine in tetrahydrofuran (1.5 mol/l) and 7 mg of 4-(dimethylamino)phenylisocyanate in 0.4 ml of tetrahydrofuran were added to a solution of 9 mg of 4-[2,5-dihydro-3-methyl-2,5-dioxo-4-[5-(piperazin-1-yl)pentyl]-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile in 0.4 ml of tetrahydrofuran, and the mixture was stirred for 8 hours at room temperature. For working-up, the reaction mixture was diluted with ethyl acetate and washed with semi-saturated sodium bicarbonate solution. After the organic phase was concentrated by evaporation, it was chromatographed with methanol/dichloromethane on silica gel, and 3 mg of the title compound was thus obtained as a yellowish oil.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].CC(C)(O)C#N.Cl>C(Cl)Cl.O>[C:16]([CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])(=[O:19])[CH2:17][CH3:18]
Reactant: O=C1CCCC(=O)C1
Reactant: CCC(=O)Cl
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)C1C(=O)CCCC1=O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a mixture of 3.0 g (0.027 mole) of 1,3-cyclohexanedione and 3.8 ml (0.027 mole) of triethylamine in 15 ml methylene chloride, there was added dropwise 2.3 ml (0.027 mole) of propionyl chloride with stirring and cooling in a room temperature water bath. After continued stirring at ambient temperature for about 4 hours, an additional 7.5 ml (0.054 mole) of triethylamine and 0.25 ml (10 mole percent with respect to enol ester) of acetone cyanohydrin were added. The mixture was stirred at ambient temperature overnight, and was then diluted with water and acidified with 6N hydrochloric acid. The phases were separated, and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4.68 g of crude product as a mixture of solid and liquid. The crude product was dissolved in methylene chloride and was extracted with 2.5N sodium hydroxide solution followed by water. The combined aqueous phases were acidified with 6 N hydrochloric acid and extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.83 g of oily product (84% of theoretical). Structure of the product was confirmed by infrared, nuclear magnetic resonance and mass spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[I:28]N1C(=O)CCC1=O>O1CCCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([I:28])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Reactant: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(I)cccc3c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-α]pyridine (100 mg, 0.346 mmol) in 4 mL of tetrahydrofuran at −78° C. under N2 was added 2.5 M n-butyllithium in hexanes (2 eq.). The mixture was stirred at −78° C. for 30 min and N-iodosuccinimide (2.2 eq.) was then added. The mixture was allowed to warm to room temperature after 30 min and was stirred at room temperature for 1 hour. The mixture was diluted with ether and washed with 1N hydrochloric acid solution. The aqueous layer was basified with 1 N sodium hydroxide solution and extracted thoroughly with ether. The combined organic layers were dried on anhydrous magnesium sulfate, filtered and evaporated. Purification by chromatography yielded 2-(4-fluorophenyl)-7-iodo-3-pyridin-4-ylpyrazolo[1,5-α]pyridine as a yellow solid. 1H NMR (CDCl3): δ 8.54 (d, 2H, J=5.8 Hz), 7.50–7.57 (m, 3H), 7.37 (d, 1H, J=7.1 Hz), 7.20 (d, 2H, J=5.8 Hz), 7.00 (t, 2H, J=8.6 Hz), 6.90 (t, 1H, J=7.8 Hz); MS m/z 416 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([O:12][C:13](OCC)([O:16]CC)[C:14]#[CH:15])[CH3:11]>C(#N)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:15]#[C:14][C:13]([O:12][CH2:10][CH3:11])=[O:16]
Reactant: Clc1ccc(Br)c(I)c1
Reactant: C#CC(OCC)(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C#Cc1cc(Cl)ccc1Br
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 55.2 %

Procedure:
A suspension of 1-bromo-4-chloro-2-iodobenzene (5.4 g, 17.0 mmol), 3,3,3-triethoxyprop-1-yne (4.4 g, 25.6 mmol), copper(I) iodide (976 mg, 5.1 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (1.19 g, 1.7 mmol) in ACN (60 mL) was degassed and backfilled with argon. The resulting mixture was treated with TEA (22.0 mL, 157.9 mmol). The reaction flask was capped with a septum and stirred at 23° C. After 90 minutes, the reaction was diluted with EtOAc (300 mL) and washed with water (150 mL). The aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, concentrated in vacuo, dissolved in EtOH (50 mL) and water (5 mL) and then treated with p-toluenesulfonic acid monohydrate (5 mg). After stirring at 23° C. for 60 minutes, the solution was concentrated, dissolved in diethyl ether (300 mL) and washed with saturated NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4, and concentrated in vacuo affording 2.7 g of ethyl 3-(2-bromo-5-chlorophenyl)propiolate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH:16]3[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#N.[C:33](=O)([O-])[O-].[NH4+:37].[NH4+:38].[ClH:39]>C(O)C>[ClH:39].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH:16]3[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)(=[NH:38])[NH2:37]
Reactant: O=C([O-])[O-]
Reactant: [NH4+]
Reactant: CCOC(=O)CN1CCC(N2CCN(c3ccc(C#N)cc3)CC2)C(CCC(=O)OC)C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCC1CN(CC(=O)OCC)CCC1N1CCN(c2ccc(C(=N)N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
550 mg of methyl 4 -[4 -(4 -cyanophenyl)-1-piperazinyl]-1-ethoxycarbonylmethyl-3-piperidinepropionate was dissolved in 20 ml of ethanol, into which hydrogen chloride was made to blow at from -10° C. to -20° C. until saturation. This was heated up to room temperature and stirred overnight, and thereafter the solvent was. removed by distillation. The residue thus obtained was dissolved in 20 ml of ethanol, and 1.0 g of ammonium carbonate was added thereto and stirred at room temperature overnight. The solvent was removed from the reaction mixture by distillation, and the resulting residue was purified by silica gel column chromatography (using an eluent of chloroform/methanol=10/1) to obtain 500 mg of ethyl 4-[4-(4-amidinophenyl)-1-piperazinyl]-1-ethoxycarbonylmethyl-3-piperidinepropionate hydrochloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][C:17]1([OH:20])[CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[NH2:15][CH2:16][C:17]1([OH:20])[CH2:19][CH2:18]1.[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:15][CH2:16][C:17]1([OH:20])[CH2:19][CH2:18]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: NCC1(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CC1
Yield: 189 %

Procedure:
1-(Aminomethyl)cyclopropanol was prepared using the method of I. L. Lysenko and O. G. Kulinkovich, Russ. J Org. Chem., 37, pp. 1238-1243 (2001). A solution of 4-chloro-3-nitroquinoline (7.28 g, 34.9 mmol) was added dropwise to a 0° C. stirred suspension of 1-(aminomethyl)cyclopropanol (36.7 mmol) and triethylamine (6.30 mL, 45.4 mmol) in dichloromethane (120 mL). The mixture was stirred at room temperature for 3 days, then was concentrated under reduced pressure. The residue was suspended in water (150 mL) and was stirred for 3 hours. The solid was isolated by filtration, washed with water (50 mL), and dried in a vacuum oven at 75° C. to afford 8.99 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopropanol as a yellow solid.
Reaction SMILES: I[C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:21]([NH:27][C:28]1[N:29]=[C:30]([OH:40])[C:31]2[CH:37]=[C:36]([C:38]#[CH:39])[CH:35]=[N:34][C:32]=2[N:33]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[C:21]([NH:27][C:28]1[N:29]=[C:30]([OH:40])[C:31]2[CH:37]=[C:36]([C:38]#[C:39][C:2]3[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=3)[CH:35]=[N:34][C:32]=2[N:33]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: COC(=O)c1cc(I)cn1[Si](C(C)C)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cn1[Si](C(C)C)(C(C)C)C(C)C
Yield: 56.7 %

Procedure:
A mixture of 3-iodo-5-methoxycarbonyl-1-triisopropylsilylpyrrole (1.222 g, 3.0 mmol), 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine (0.851 g, 3.15 mmol), Pd(PPh)2C12 (105 mg, 0.15 mmol), cuprous iodide (2 g mg, 0.15 mmol), and triethylamine (0.5 mL) in acetonitrile (50 mL) was heated at reflux for 4 hours. The resulting solution was cooled, filtered, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with hexanes:ethyl acetate(2:1). The first major fraction is unchanged starting material (270 mg, 32%); the subsequent major fluorescent fractions were combined and concentrated in vacuo to give methyl 4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethynyl]1-triisopropylsilylpyrrole-2-carboxylate as a pale yellow solid (935 mg, 57%, mp 163-165° C.): 1H NMR (CDCl3) δ 8.90 (br s, 1H), 8.52 (d, 1H, J=2.4 Hz), 7.35 (d, 1H, J=1.4 Hz), 7.23 (d, 1H, J=1.4 Hz), 3.79 (s, 3H), 1.75 (sept, 3H, J=7.6 Hz), 1.31 (s, 9H), 1.10(d, 18H, J=7.6 Hz).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)=[O:32])=[O:22])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]([C:25]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=2[NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][CH:17]=2)=[O:22])=[O:32])=[N:35][CH:36]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 25 %

Procedure:
The mixture of the compound of (2-{[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide example 12 (0.5 mmol) in trifluoroacetic acid (5 ml) was stirred at r.t. for 5 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-(5-chloro(2-pyridyl))(5-chloro-2-{[4-(2-sulfamoylphenyl)-phenyl]carbonylamino}phenyl)-carboxamide as a white powder (68 mg, 25%). MS found for C25H18Cl2N4O4S
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:19](OC1C=CC([N+]([O-])=O)=CC=1)=[O:20].[C:31]1([C:37]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:41]3[CH2:42][NH:43][CH2:44][CH2:45][N:40]3[C:39](=[O:46])[O:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[O:46]=[C:39]1[N:40]2[CH2:45][CH2:44][N:43]([C:19]([NH:1][CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[O:20])[CH2:42][CH:41]2[C:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[O:38]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: NCc1ccncc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccncc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
4-(Aminomethyl)pyridine (0.50 g, 4.6 mmol) was dissolved in tetrahydrofuran (5 mL). With ice cooling, diisopropylethylamine (1.5 mL) and 4-nitrophenyl chloroformate (1.0 g, 5.0 mmol) were added thereto, and the mixture was stirred at 0° C. for 30 minutes. Next, hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.15 g, 0.51 mmol) was added thereto, and the resulting mixture was stirred for 16 hours while elevating the temperature from 0° C. to room temperature. The reaction solution was concentrated under reduced pressure, an aqueous saturated sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and water, and concentrated under reduced pressure. The residue was purified with amino silica gel column chromatography (ethyl acetate) and powder was formed from hexane to obtain the title compound (0.12 g, yield 56%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Li]CCCC.[S:15](=[O:17])=[O:16].C1C(=O)N(Cl)C(=O)C1.[F:26][C:27]([F:50])([F:49])[C:28]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH:41]2[C:46]#[C:47][CH3:48])=[CH:36][CH:35]=1)([OH:33])[C:29]([F:32])([F:31])[F:30].C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([S:15]([N:43]2[CH2:44][CH2:45][N:40]([C:37]3[CH:36]=[CH:35][C:34]([C:28]([OH:33])([C:29]([F:30])([F:31])[F:32])[C:27]([F:50])([F:26])[F:49])=[CH:39][CH:38]=3)[CH:41]([C:46]#[C:47][CH3:48])[CH2:42]2)(=[O:17])=[O:16])=[CH:3][C:4]=1[F:9]
Reactant: O=S=O
Reactant: CC#CC1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: Fc1cc(Br)cnc1Cl
Agent: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC#CC1CN(S(=O)(=O)c2cnc(Cl)c(F)c2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
A 50-mL round-bottomed flask solution was cooled to −78° C. and charged with 5-bromo-2-chloro-3-fluoropyridine (259 mg, 1.23 mmol, Asymchem Laboratories, Inc., Morrisville, N.C.) and diethylether (10 mL). n-BuLi (0.49 mL, 2.5M solution in hexanes, 1.23 mmol) was added and after 5 min. Sulfur dioxide (52.5 mg, 0.819 mmol, Sigma-Aldrich, St. Louis, Mo.) was then bubbled through the cold solution for 1 min. The mixture was then allowed to warm to room temperature and concentrated. To this was solid was added CH2Cl2 (10 mL) and NCS (152 mg, 1.15 mmol, Alfa Aesar, Ward Hill, Mass.) added. After 20 min, 1,1,1,3,3,3-hexafluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol (300 mg, 0.819 mmol, Example 241, Step 3) and triethylamine (0.457 mL, 3.28 mmol) were added to the reaction mixture. After a further 10 min at room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to give an oil that was purified via column chromatography on silica gel (0 to 100% EtOAc in hexanes) to give 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (165 mg) as a mixture of two isomers
Reaction SMILES: Br.[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Br.[OH-].[K+].CCOCC>CN(C=O)C.O>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][N:4]1[C:3]([CH3:2])=[C:7]([CH3:8])[N:6]=[CH:5]1
Reactant: Cc1nc[nH]c1C
Reactant: Clc1ccccc1CBr
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ncn(Cc2ccccc2Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a solution of 4.89 g (0.027 mol) of 4,5-dimethylimidazole hydrobromide and 5.7 g (0.028 mol) of 2-chlorobenzyl bromide in 20 ml of DMF is added 6 ml of 50% potassium hydroxide aqueous solution dropwise. The reaction mixture is stirred at room temperature under nitrogen overnight. The reaction mixture is then poured into ether (100 ml)/water (50 ml). The ether layer is separated, washed with water (10 ml×2), dried over anhydrous sodium sulfate and evaporated in vacuo. The raw material is subjected to chromatography on silica gel using dichloromethane-methanol (10:1) as eluant to give 2.67 g (0.012 mol, 44%) of 1-(2-chlorobenzyl)-4,5-dimethylimidazole as a pale yellow oil. LC-MS (M++1): 221.2; 1H-NMR (δ, CDCl3): 2.00 (3H, s), 2.20 (3H, s), 5.07 (2H, s), 6.59 (1H, dd, J=9.2, 2), 7.17 (1H, td, J=8, 1.2), 7.23 (1H, td, J=8, 1.6), 7.38 (2H, dd, J=7.2, 1.6).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)Cl.[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:9]1[C:4]2[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: Nc1cccc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Yield: 63 %

Procedure:
Reaction of 6-fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (0.60 g, 3.6 mmol) with POCl3, followed by reaction of the crude 4,6-dihalo compound with 3-bromoaniline gives 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (0.73 g, 63%). 1H NMR (DMSO) δ 10.09 (1H, brs), 8.96 (1H, s), 8.75 (1H, s), 8.25 (2H, m), 7.90 (1H, brd, J=6.5 Hz), 7.44-7.34 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:28])[CH3:27])[CH:20]=4)[CH2:14][CH2:13]3)[C:11](=S)[NH:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:28])[CH3:27])[CH:20]=4)[CH2:14][CH2:13]3)[C:11]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[N:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CN
Reactant: CC(C)Oc1cccc(CN2CCC3(CC2)C(=S)NC(=O)N3c2cccc(F)c2)c1
Solvent: CS(C)=O
Product: CC(C)CNC1=NC(=O)N(c2cccc(F)c2)C12CCN(Cc1cccc(OC(C)C)c1)CC2
Temperature: 110 °C

Procedure:
To a solution of 1-(3-Fluoro-phenyl)-8-(3-isopropoxy-benzyl)-4-thioxo-1,3,8-triaza-spiro[4.5]decan-2-one SNS-1 (21.4 mg, 0.05 mmol) in DMSO (1 mL) was added isobutyl amine (36.5 mg, 0.5 mmol). The reaction mixture was heated at 110° C. for 12 hr. The crude was purified by preparative HPLC to provide (14-8).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][N:5]([S:7][C@@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[NH:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:45][CH2:46][C:47]([NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55](=[N:59][O:60][CH3:61])[C:56]([OH:58])=O)[N:54]=1)=[O:48]>CC(C)=O>[Cl:45][CH2:46][C:47]([NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55](=[N:59][O:60][CH3:61])[C:56]([NH:13][C@H:9]2[C@H:8]([S:7][N:5]3[CH2:6][N:2]([CH3:1])[N:3]=[N:4]3)[NH:11][C:10]2=[O:12])=[O:58])[N:54]=1)=[O:48]
Reactant: CN1CN(S[C@@H]2NC(=O)[C@H]2NC(c2ccccc2)(c2ccccc2)c2ccccc2)N=N1
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1SN1CN(C)N=N1)c1csc(NC(=O)CCl)n1
Yield: 55.9 %

Procedure:
Following the procedure of Reference Example 66B, solution of 1.12 g of (3R,4S)-4-(1-methyl-1H-tetrazol-4-yl)thio-3-tritylamino-2-oxoazetidine in 5 ml of acetone, 0.491 g of p-toluenesulfonic acid monohydrate and 0.788 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid is treated to give 0.650 g of (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-(1-methyl-1H-tetrazol-4-yl)thio-2-oxoazetidine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16]1.[Sn](Cl)(Cl)(Cl)Cl.Cl.Cl[CH2:31]Cl>>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:12]([CH2:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][O:2][C:3]=3[CH:4]=2)=[O:13])[CH:21]=[CH:20][C:19]=1[O:15][CH3:31]
Reactant: c1ccc2c(c1)OCO2
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: ClCCl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Product: COc1ccc(C(=O)Cc2ccc3c(c2)OCO3)cc1OC
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 3,4-dimethoxyphenylacetyl chloride (3.25 g, 15 mmol) in 15 mL freshly distilled dry dichloromethane was added dropwise to a stirred mixture of 1,3-benzodioxole (1.83 g, 15 mmol) and tin(IV) chloride (4.6 g, 17.6 mmol) in 15 mL dichloromethane at -10° C. The mixture was then allowed to rise to room temperature and was stirred for an additional 2 h. The reaction mixture was then poured into 25 mL 6 N HCl and stirred for 16 h. The organic phase was then separated and the aqueous phase was extracted three times with 20 mL aliquots of dichloromethane. The combined dichloromethane extract was washed successively with 20 mL of 0.1 N NaOH and 20 mL distilled water. The dichloromethane extract was then dried (Na2SO4), filtered, and evaporated to give a cream colored solid. The crude product was crystallized from ethanol to give 3.0 g of white needles of 11b in 66% yield; mp 110-111° C.; IR (Nujol) 2725, 1675, 1589,1519; 1H NMR δ 3.80 (s, 3H), 3.81 (s, 3H), 4.09 (s, 2H), 5.96 (s, 2H), 6.76 (m, 4H), 7.42 (d, I H, J=1.5), 7.58 (dd, 1H, J=6.4, 1.5); 13C NMR δ 45.3, 56.3, 102.3, 108.3, 108.7, 111.8, 112.7, 112.9, 121.9, 125.4, 127.7, 131.8, 148.4, 148.6, 149.4, 152.2, 196.4; Anal. calcd for C17H16O5 : C, 67.99, H, 5.37; Found: C, 67.98. H, 5.32.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]([OH:8])[CH:5]([CH3:7])[CH3:6].C(N(C(C)C)CC)(C)C.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]([O:8][CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[CH:5]([CH3:7])[CH3:6]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)[C@@H](O)C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](OCOCC[Si](C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl-2-(S)-hydroxy-3-methylbutanoate (1.0 eq; J. Org. Chem. (1997), 62(7), 2292-2297, incorporated herein by reference) in dichloromethane was stirred with diisopropylethylamine (2.0 eq) under nitrogen. 2-Trimethylsilylethoxymethyl chloride (3 eq; Aldrich) was added dropwise via syringe. The solution was stirred at room temperature for 17 hours. The solution was washed with 1.0N HCl, and the water layer was back extracted with dichloromethane. The organics were combined, dried over Na2SO4, and the solvents removed in vacuo. The residue was purified via radial chromatography using 20% ethyl acetate in hexanes affording the title intermediate as a clear oil.