Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[H-].[Na+].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH2:15][CH:17]1[CH2:18][O:19]1
Reactant: ClCC1CO1
Reactant: Oc1cc(C(F)(F)F)ccc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(I)c(OCC2CO2)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A sample of 20 g (0.069 mole) of 2-iodo-5-trifluoromethylphenol was added in portions to a suspension of 0.07 mole of NaH (from 3.36 g of 50% NaH which had been washed free of oil with hexane) in 150 ml of dry DMF under N2. When gas evolution had ceased, a 27 ml (0.347 mole) sample of epichlorohydrin was added dropwise at 5° C. The mixture was heated at 60° C. for 3 hr and allowed to stand at 25° C. for 16 hr. A precipitate was removed by filtration. The filtrate was concentrated to dryness in vacuo. The residue was taken up in ether, washed with water and brine, dried (K2CO3) and the solvent evaporated in vacuo to give 20.4 g (86% yield) of [(2-iodo-5-trifluoromethylphenoxy)methyl]oxirane as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH:23]=O)([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].C[O:30][C:31](=[O:33])[CH3:32].[Li+].[OH-].O>C1COCC1.CO>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH:23]=[CH:32][C:31]([OH:33])=[O:30])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: COC(C)=O
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C=O)(CCC3)C4)nc2n(CCC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCCC(C=CC(=O)O)(CCC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carbaldehyde (355 mg) was taken in THF (25 ml). Triphenyl-□□-phosphanylidene)-acetic acid methyl ester (614 mg) was added and refluxed overnight. Next day another 460 mg of Triphenyl-□□-phosphanylidene)-acetic acid methyl ester was added and refluxed for 24 hrs. Cooled to RT LiOH (210 mg), water (2 ml), MeOH (5 ml) were added and stirred at rt overnight. Solvent was removed under reduced pressure. Diluted with water (25 ml), extracted with ethyl acetate (3×25 ml). Aqueous layer was acidified with 1 N HCl and extracted with ethyl acetate (3×50 ml), dried over Na2SO4 and concentrated. Yield 254 mg. Mass (ES+ 429).
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[C:9]([S-:11])#[N:10].[Na+]>CC(CC)=O>[S:11]([CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4])[C:9]#[N:10]
Reactant: CC(=O)C(Cl)CCCl
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)C(CCCl)SC#N
Yield: 96.3 %

Procedure:
A solution of 155.5 g (1 mole) of 3,5-dichloro-2-pentanone with 83 g (1.024 moles) of sodium rhodanide in 1 liter of methyl-ethyl-ketone is boiled for 1 hour under stirring. Then the procedure described in Example 1 is followed. 171 g (96.2%) of 3-thiocyanato-5-chloro-2-pentanone are obtained, which after distillation identical in all respect with the product of Example 1.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]([CH3:25])[CH2:11][CH2:12][CH2:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:15]#[N:16].[C:26](=[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:28])[CH3:27].[ClH:40]>C1COCC1.CCCCCCC.O1CCCC1.O>[ClH:40].[C:15]([C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)([CH2:13][CH2:12][CH2:11][N:10]([CH3:9])[CH3:25])[C:26]([CH:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:27])[CH3:28])#[N:16]
Reactant: COc1cccc(C(C#N)CCCN(C)C)c1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)C(C#N)(CCCN(C)C)c1cccc(OC)c1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A nitrogen atmosphere was applied to a reaction vessel and 50 ml of dry tetrahydrofuran is added. The solvent was cooled to less than −40° C. and 32 mmoles of lithium diisopropylamide in tetrahydrofuranne-heptane was added (16 ml of a 2 M solution). A solution of 6.97 g (30 mmoles) of α-[3-(dimethylamino)propyl]-3-methoxybenzeneacetonitrile in 30 ml of tetrahydrofuran was added at less than −20° C. and left at this temperature for 30 min. The mixture was then cooled to −50° C. and a solution of 6.62 g (33 mmoles) of diethyl isopropylidenemalonate in 30 ml of tetrahydrofuran was added to the reaction mixture at a rate such that the temperature did not exceed −50° C. The mixture was stirred at −50° C. for 30 min and the cold reaction mixture added to a stirred solution of 30 ml of aqueous hydrochloric acid (36% w/w) in 100 ml of water cooled to 10° C. The mixture was extracted twice with toluene and the toluene phase is back extracted with a solution of 2 ml of hydrochloric acid (36% w/w) in 8 ml of water. The aqueous acidic extract was combined with the aqueous acidic phase from above and extracted twice with 50 ml portions of methylene chloride. The combined methylene chloride extracts were washed with water and the methylene chloride phase filtered and concentrated to low volume by distillation at atmospheric pressure. A 100 ml portion of ethyl acetate was added and the resulting slurry cooled to 5–10° C. The resulting solid was collected by filtration, washed with ethyl acetate and dried at 50° C. to give 10.1 g of white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])=[O:5])[CH3:2]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)C1Cc2ccccc2N1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)N1c2ccccc2CC1C(=O)OCC

Procedure:
To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (4.78 g., 25.0 mmole), triethylamine (2.7 g., 26.7 mmole), and anhydrous ether (500 ml) was added dropwise methacryloyl chloride (2.9 g., 27.7 mmole) dissolved in a small amount of ether. After the completion of the addition, the ice bath was removed, and the reaction mixture was stirred for 4 hours. The precipitate which separated was removed by filtration, and the filter residue was washed with ether. The combined filtrate and washing were washed with water (two 700-ml portions), then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the product as an oil. The product was purified by preparative HPLC (Prep LC/System 500, Waters Associates), using a micro porasil column eluted with a mixture of hexane (95%) and ethyl acetate (5%). The crude oil may be used directly in the following reaction (Example 2).
Reaction SMILES: C[O-].[Na+].C(OC(=O)C([O:10][CH2:11][CH3:12])=O)C.[N+:14]([C:17]1C=[CH:21][CH:20]=[CH:19][C:18]=1C)([O-:16])=[O:15].O>C(O)C>[N+:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=1[CH:11]=[O:10])([O-:16])=[O:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=Cc1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
383 g (7.1 mols) of sodium methylate are dissolved in ethanol and 985 g (6.75 mols) of oxalic acid diethyl ester and 925 g (6.75 mols) of 2-nitrotoluene are poured in. The mixture is heated under reflux for 30 minutes and is allowed to cool, 300 ml of ice water are next added cautiously and after the exothermic reaction has subsided 1,600 ml of water are added. After boiling additionally for 90 minutes under reflux, the mixture is steam-distilled until two phases no longer pass over. The organic phase is separated from the distillate and 310 g of 2-nitrotoluene are recovered from it. The residual aqueous phase of the distillate is filtered, 600 g of (anhydrous) sodium carbonate and 2,000 ml of toluene are added and the mixture is cooled to +3° C. 650 g of solid potassium permanganate are added over the course of 70 minutes and the reaction temperature is kept at between +2° and +6° C. The mixture is stirred for a further 45 minutes at +5° C and then warmed to 40° C, and 50% strength sulphuric acid is then added dropwise (gas being evolved). The exothermic reaction is kept at 35°- 40° C by cooling. Insoluble material is then filtered off and the toluene phase is separated from the filtrate. The filter residue is washed with hot toluene and the combined toluene phases are extracted by shaking with 15% strength sodium carbonate solution and with water and are then dried with the sodium sulphate. On concentrating the toluene phase in vacuo, 2-nitrobenzaldehyde is obtained as a viscous oil which crystallizes immediately on cooling. Melting point 40°- 41° C.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[N:10]2[C:5]([C:6]([CH3:14])([CH3:13])[O:7][CH2:8][CH2:9]2)=[N:4][C:3]=1[C:15]([O:17]CC)=O.C(N(CC)CC)C.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C(O)C>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:15]([C:3]2[N:4]=[C:5]3[N:10]([C:11](=[O:12])[C:2]=2[OH:1])[CH2:9][CH2:8][O:7][C:6]3([CH3:13])[CH3:14])=[O:17])=[CH:30][CH:29]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 35 °C
Reaction time: 6 h
Yield: 91.2 %

Procedure:
Additional procedure. Ethyl 3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (50 g, 0.186 mol) and ethanol SDA3A (500 mL) was added to a 1 L round bottom flask equipped with a mechanical stirrer, nitrogen inlet-outlet, temperature probe, and condenser. Triethylamine (18.86 g, 0.186 mol) was added to the slurry. The resulting solution was heated to 35° C. followed by slow addition of 4-fluorobenzylamine (35.0 g, 0.279 mol). The thick slurry was heated at 78° C. with stirring for 6 h. The reaction mixture was polish filtered and the filtrate reheated to 70° C. The pH was adjusted to about 1.0 by slow addition of 1N HCl (405 mL). The thick slurry was cooled to 20–25° C., the solids filtered off, washed twice with ethanol SDA 3A (each 250 mL) and twice with water (each 500 mL). The white solid was dried in vacuo at 50–55° C. to afford N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide (58.9 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1
Reactant: CN(C)CCCl
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 96 h

Procedure:
38.9 g of N-methylsulphonyl-4-nitroaniline are dissolved in 2.0 l of acetone, 51.9 g of 1-chloro-2-dimethylamino-ethane, 77.4 g of potassium carbonate and 5.0 g of sodium iodide added and the mixture is stirred for a total of 4 days at 50° C., adding, after 12 hours, a further 25.9 g of 1-chloro-2-dimethylamino-ethane, 49.8 g of potassium carbonate and 5.0 g of sodium iodide in 500 ml of acetone and, after 36 hours, a further 26.0 g of 1-chloro-2-dimethylamino-ethane, 50.0 g of potassium carbonate and 5.0 g of sodium iodide in 100 ml of acetone. After this time the mixture is filtered and the filtrate is evaporated down. The residue is stirred with ether, suction filtered and dried at 40° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(OCC)C.O.C([O-])([O-])=O.[K+].[K+]>[CH3:18][S:19]([O:10][CH2:9][CH2:8][C:7]#[C:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCC#Cc1cccs1
Reaction time: 0.5 h

Procedure:
To a solution of 750 mg of 1a and 1 ml of triethyl amine in 15 ml of diethyl ether, was added dropwise at 0° C. 400 μl of methanesulfonyl chloride in 5 ml of diethyl ether. The reaction mixture was stirred for ½ hr and then diluted with 30 ml of water and 5 ml of 1M K2CO3. The product was extracted with diethyl ether and the combined extracts were once washed with water, dried and concentrated, to provide 1.2 g of mesylate 1b; Rf 0.50 (heptane/ethyl acetate 1/1), MS-ESI: [M+1] 231.07.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[N:18]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O1CCCC1.O>[Br:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][N:18]=[C:4]2[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(F)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2n[nH]c3ccc(Br)cc23)cc1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a solution of 2-amino-5-bromo-4′-fluorobenzophenone (13.50 g, 45.9 mmol) in 6 N hydrochloride solution (400 mL) and tetrahydrofuran (500 mL) at −15° C. was slowly dropped a solution of sodium nitrite (4.12 g, 59.7 mmol) in water (20 mL). After stirring for 30 minutes in cold bath, to the reaction mixture was added a solution of tin(II) chloride dihydrate (28.48 g, 126 mmol) in concentrated hydrochloric acid (70 mL) dropwise. A white solid precipitated immediately. After 30 minutes, the white solid was filtered, dissolved in ethyl acetate, and washed with saturated sodium bicarbonate. The filtrate was neutralized with sodium hydroxide and extracted with dichloromethane. The ethyl acetate and dichloromethane layers were combined, dried over magnesium sulfate, and concentrated. Crystallization from ethyl acetate gave the title compound as a white solid (5.266 g). The mother liquor was then purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide another batch of the title compound (3.429 g, total 8.695 g, 65% yield). 1H NMR (CDCl3) δ 10.54 (br s, 1H), 8.11 (m, 1H), 7.87-7.92 (m, 2H), 7.50 (m, 1H), 7.34 (d, 1H), 7.20-7.26 (m, 2H); ES-MS (m/z) 293 [M+3]+, 291 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](CC2C=C3C(=C4C=CC=CC=24)N=CNC3=O)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][C:31]2[CH:32]=[C:33]3[C:38](=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=24)[N:37]=[CH:36][NH:35][C:34]3=[O:45])=[CH:28][CH:27]=1.IC1C=NC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>C1COCC1.CS(C)=O.[Cu]I>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][C:31]2[CH:32]=[C:33]3[C:38](=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=24)[N:37]=[CH:36][NH:35][C:34]3=[O:45])=[CH:46][CH:47]=1.[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][C:31]2[CH:32]=[C:33]3[C:38](=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=24)[N:37]=[CH:36][N:35]([C:5]2[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=2)[C:34]3=[O:45])=[CH:46][CH:47]=1
Reactant: O=c1[nH]cnc2c1cc(Cc1ccc(Cl)nc1)c1ccccc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: COc1ccc(Cc2cc3c(=O)[nH]cnc3c3ccccc23)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(Cc2cc3c(=O)n(-c4cccnc4)cnc3c3ccccc23)cc1
Temperature: 120 °C

Procedure:
6-(4-methoxybenzyl)benzo[h]quinazolin-4(3H)-one was prepared by the same procedure as described for 6-[(6-chloropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one in Example 1. To a solution of 6-(4-methoxybenzyl)benzo[h]quinazolin-4(3H)-one (0.030 g, 0.095 mmol) and 3-iodopyridine (0.058 g, 0.28 mmol) in 2 mL of THF and 1 mL of DMSO under an atmosphere of nitrogen was added cesium carbonate (0.19 mL, 1 N aqueous, 0.19 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (1.3 mg, 0.0095 mmol), and copper(I) iodide (1.8 mg, 0.095 mmol). The reaction was heated at 120° C. for 15 h, cooled to rt, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 393.9 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.07 (d, J=8.0, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.14 (d, J=7.6 Hz, 1H), 8.07 (d, J=9.6 Hz, 2H), 7.95 (s, 1H), 7.74-7.54 (m, 5H), 4.57 (s, 4.21-4.09 (m, 1H), 3.92 (s, 3H), 2.20-2.18 (m, 1H), 2.03-1.96 (m, 1H), 1.95-1.83 (m, 2H), 1.58-1.39 (m, 3H), 1.29-1.18 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH3:13])[CH:3]=1.[CH2:14]([S:16]([NH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)(=[O:18])=[O:17])[CH3:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][N:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[C:20]([NH:19][S:16]([CH2:14][CH3:15])(=[O:17])=[O:18])[CH:21]=[CH:22][CH:23]=2)[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[C:5]1=[O:12]
Reactant: CCS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cn1cc(Cl)c2cnccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cccc(-c2cn(C)c(=O)c3ccncc23)c1
Yield: 6.6 %

Procedure:
A mixture of 4-chloro-2-methyl-2,6-naphthyridin-1-one (50.0 mg, 0.26 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (88.0 mg, 0.38 mmol), Pd(dppf)Cl2 (15.3 mg, 0.026 mmol) and K3PO4 (190 mg, 0.9 mmol) in dioxane (3 mL) and water (0.5 mL) was microwaved at 120° C. under microwave for 2 h. Purification by silica gel chromatography on (PE:EA=10:1 to 1:1) followed by preparative HPLC gave the title compound (5.9 mg, 6.8%) as a yellow solid. 1H NMR (Methanol-d4, 400 MHz) δ 8.99 (brs, 1H), 8.71 (d, J=6.0 Hz, 1H), 8.39 (d, J=5.6 Hz, 1H), 7.62 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.41-7.40 (m, 1H), 7.36 (dd, J1=8.0 Hz, J2=1.2 Hz, 1H), 7.29 (d, J=5.6 Hz, 1H), 3.72 (s, 3H), 3.17 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H). LCMS: 344.1 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[CH:26])=[N:23][CH:24]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([CH3:11])[CH:3]=3)=[N:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Cc1cc(I)ccc1CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 16 mg (0.02 mmol) of PdCl2(dppf) and 4 mg (0.02 mmol) of CuI were added to a repeatedly degassed solution of 940 mg (1.79 mmol) of 2-(4-iodo-2-methylphenyl)ethanol, 383 mg (1.79 mmol) of 5-(4-chlorophenyl)-2-ethynylpyridine (IP 13), and 0.52 mL (3.77 mmol) of triethylamine in 8 mL of acetonitrile and the mixture was stirred overnight at RT. The precipitate was suction filtered and washed with acetonitrile. Yield: 270 mg (43% of theoretical); C22H18ClNO (M=347.837); calc.: molpeak (M+H)+:348/50 (Cl); found: molpeak (M+H)+:348/50 (Cl); HPLC-MS: 6.15 minutes (method H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:20])[N:4]=1.I([O-])(=O)(=O)=[O:22].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:20][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:3]([CH:2]=[O:22])=[N:4]2
Reactant: Fc1cccc(-c2nc3c(Cl)cccc3nc2CBr)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(bromomethyl)-5-chloro-3-(3-fluorophenyl)quinoxaline (Prepared in Example 95, 0.8089 g, 2.301 mmol) and sodium metaperiodate (0.9842 g, 4.601 mmol) in DMF (15.34 mL, 2.301 mmol) was heated at 150° C. with stirring. After 5 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with sat'd Na2S2O3 (50 mL×1) and brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 20 min as eluent to give 5-chloro-3-(3-fluorophenyl)quinoxaline-2-carbaldehyde as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (1 H, s), 8.31 (1 H, dd, J=8.2, 1.2 Hz), 8.25 (1 H, dd, J=7.4, 1.2 Hz), 7.99 (1 H, dd, J=8.4, 7.6 Hz), 7.56-7.70 (3 H, m), 7.38-7.46 (1 H, m); LC-MS (ESI) m/z 287.0 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([C:12]2[C:17]([CH3:18])=[C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=3[F:30])[N:15]=[CH:14][N:13]=2)[CH2:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]>C1COCC1>[CH:42]([O:41][C:39]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:12]2[C:17]([CH3:18])=[C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][C:21]=3[F:30])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:8]1)=[O:40])([CH3:44])[CH3:43]
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1N(CC1CCNCC1)C1CC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1N(CC1CCN(C(=O)OC(C)C)CC1)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
A mixture of cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-piperidin-4-ylmethyl-amine (65 mg, 0.15 mmole) and triethylamine (23 mg, 0.225 mmole) in 2 mL THF was stirred at room temperature for 10 minutes. Into this mixture was added drop-wise isopropyl chloroformate (0.225 mmole). The mixture was quenched with water, extracted with ethyl acetate, and dried in vacuum to give Compound D2 as a yellow solid (65 mg, 83%). 1H NMR (CDCl3, 400 MHz) δ 0.69-0.64 (m, 2H), 0.83-0.88 (m, 2H), 1.12-1.15 (m, 2H), 1.23 (d, J=6.3 Hz, 6H), 1.72 (d, J=13.1 Hz, 2H), 1.94-2.02 (m, 1H), 2.04 (s, 3H), 2.73 (t, J=12.4 Hz, 2H), 2.97-3.17 (m, 1H), 3.10 (s, 3H), 3.49-3.55 (m, 2H), 4.09-4.23 (m, 2H), 4.90 (sept, J=6.3 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 7.76-7.80 (m, 2H), 8.12 (s, 1H). Exact mass calculated for C25H33FN4O5S 520.2, found 521.5 (MH+).