Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[CH:42]1([CH2:48][S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)CC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)CC3CCCCC3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 80.3 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0843 g, 0.183 mmol) was dissolved in dichloromethane (3.0 mL), and the solution was treated with triethylamine (0.127 mL, 0.913 mmol) and cyclohexylmethanesulfonyl chloride (0.108 g, 0.548 mmol) to obtain 4-cyclohexylmethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0914 g, yield 80%).
Reaction SMILES: C[C:2]#[N:3].[CH2:4]([Li])CCC.[Cl:9][C:10]1[C:21]([Cl:22])=[CH:20][C:13]2[NH:14][C:15]([C:17](=[O:19])[CH3:18])=[N:16][C:12]=2[CH:11]=1.O>C1COCC1>[Cl:22][C:21]1[C:10]([Cl:9])=[CH:11][C:12]2[NH:16][C:15]([C:17]([OH:19])([CH3:4])[CH2:18][C:2]#[N:3])=[N:14][C:13]=2[CH:20]=1
Reactant: CC#N
Reactant: [Li]CCCC
Reactant: CC(=O)c1nc2cc(Cl)c(Cl)cc2[nH]1
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(CC#N)c1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
CH3CN was added to a solution of n-butyl lithium in THF (8 ml) at −78° C. and the mixture was stirred at −78° C. for 45 minutes. To this solution was added 1-(5,6-dichloro-1H-benzimidazol-2-yl)-ethanone in THF (6 ml) and the resulting mixture was stirred at −78° C. for an addition ½ hour. After stirring at 0° C. for 6 hrs, water was added, the resulting solution was extracted with EtOAc, the organic layer was washed with brine and then dried over anhydrous Na2SO4. Solvent was distilled off under reduced pressure. Column chromatography (silica gel, EtOAc/hexanes 10% to 50%) yielded the title product as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11](B(O)O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Br[C:16]1[S:20][C:19]([N:21]([CH3:32])[CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[N:18][N:17]=1>>[CH3:32][N:21]([CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]1)[C:19]1[S:20][C:16]([C:11]2[C:2](=[O:1])[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:17][N:18]=1
Reactant: O=c1[nH]c2ccccc2cc1B(O)O
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Product: CN(c1nnc(-c2cc3ccccc3[nH]c2=O)s1)C1CC(C)(C)NC(C)(C)C1

Procedure:
Following a similar procedure as described for Step 3 in Example 101, (2-oxo-1,2-dihydroquinolin-3-yl)boronic acid and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (858 mg, 2.57 mmol) were reacted to provide the crude product, which was purified by preparative HPLC under basic condition to give 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one (14 mg, MS: 398.2 [M+H+], LCMS Rt=0.51 min (LCMS method D); 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.74 (s, 1H), 7.67-7.80 (m, 1H), 7.47-7.57 (m, 1H), 7.31 (d, J=8.08 Hz, 1H), 7.19-7.27 (m, 1H), 4.34 (br. s., 1H), 2.99 (s, 3H), 1.71 (dd, J=12.63, 3.03 Hz, 2H), 1.50 (t, J=12.38 Hz, 2H), 1.28 (s, 6H), 1.10-1.23 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[CH:19]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[N:17]=[CH:19][NH:18][C:4]=2[CH:3]=1
Reactant: CCOC([O-])[O-]
Reactant: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Oc2cc3nc[nH]c3cc2Br)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A solution of 4-bromo-5-(2,4-difluorophenoxy)benzene-1,2-diamine (0.090 g, 0.28 mmol) in tetrahydrofuran (1.1 mL) was treated with ethyl orthoformate (0.142 mL, 0.857 mmol) followed by p-toluenesulfonic acid monohydrate (0.005 g, 0.03 mmol) and stirred at 50° C. for 1 h. The reaction mixture was concentrated and diluted with ethyl acetate and saturated sodium bicarbonate. The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography (100% hexanes to 100% EtOAc) gave the desired product (69 mg, 74%). LCMS calculated for C13H8BrF2N2O (M+H)+: m/z=325.0, 327.0. found: 325.0, 327.0.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:4]=1.[C:24](OC(=O)C)(=O)C.N1CCCCC1.[OH-].[K+].[OH-].[NH4+]>C1(C)C=CC=CC=1.CO>[CH3:24][O:10][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:23])[CH3:1])=[CH:8][CH:7]=2)[C:11]2[C:12](=[CH:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)[C:13](=[O:15])[O:14]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CO
Product: COC1(c2ccc(N(C)C)cc2)OC(=O)c2cc(N(C)C)ccc21
Temperature: 25 °C

Procedure:
A mixture of 6.3 g of 2-(4-dimethylaminophenyl)carbonyl-5-dimethylaminobenzoic acid and 150.0 ml of acetic anhydride was stirred for approximately fifteen minutes at ambient temperature. Slowly, 10.0 ml of piperidine and 10.0 ml of methyl alcohol were added to the mixture. Two grams of potassium hydroxide was added to complete the solution. The temperature rose to 55° C. with the addition of the potassium hydroxide. The resulting solution was allowed to stir overnight with gradual return to ambient temperature. Slowly, this solution was poured into a mixture of five percent aqueous ammonium hydroxide and toluene. After separation, the toluene layer was washed first with water and then with saturated aqueous sodium chloride solution. The resulting toluene layer was evaporated to dryness. The residue was slurried in 100.0 ml of isopropyl alcohol and the separated solid was collected by filtration, washed three times, each with 30.0 ml of isopropyl alcohol, and dried to obtain 4.0 g of 3-methoxy-3-(4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula II: R0 =R=R2 =R5 =H; R1 =N(CH3)2 ; R4 =R4' =Y=CH3 ; X=O), a pale green solid which melted at 150° to 153° C. A significant infrared maximum appeared at 1765 cm-1 (C=O;s). The nuclear magnetic resonance spectrum was in accord with the assigned structure. A toluene solution of the product spotted on an acidic clay-coated paper developed a green-colored image.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([OH:12])[C@@H:4]([OH:11])[C@H:5]([OH:10])[C@@H:6]([OH:9])[CH:7]=O.[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[C:32](Cl)(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>>[F:1][CH2:2][C@H:3]1[O:12][CH:7]([N:31]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@H:6]([OH:9])[C@@H:5]([OH:10])[C@@H:4]1[OH:11]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CF
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)C1O[C@H](CF)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
18.2 g of 6-deoxy-6-fluoro-D-glucose, 13.5 g of octadecylamine and 7 g of oleoyl chloride were reacted as described in Example 15 and the product was worked up.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1C(=O)C2CCCC(=C2)[C:16]1=[O:25].[F:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH2:34])([CH3:33])[CH3:32])=[CH:29][CH:28]=1.CN1[CH2:43][CH2:42][O:41]CC1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:6]1[CH2:7][CH2:2][CH2:3][CH2:4][C:43]=1[C:42]([NH:34][C:31]([C:30]1[CH:29]=[CH:28][C:27]([F:26])=[CH:36][CH:35]=1)([CH3:33])[CH3:32])=[O:41]
Reactant: CN1CCOCC1
Reactant: CC(C)(N)c1ccc(F)cc1
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: CC(C)(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide (1.00 g, 2.75 mmol), 4-fluorocumylamine (0.600 g, 3.92 mmol), N-methylmorpholine (0.330 g, 3.26 mmol), and benzene (10 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from ethyl acetate/acetone to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-fluorocumyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.417 g, 29.3% yield).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:22])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:23](Cl)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:22][C:23](=[O:25])[CH3:24])[S:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2ccc(C(C)(C)C)cc2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 50.7 %

Procedure:
To a solution of [4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.40 g, 1.29 mmol) and 4-dimethylaminopyridine (0.05 g, 0.39 mmol) in N,N-dimethylacetamide (4 mL) was added acetyl chloride (0.15 g, 1.94 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. Crude crystals were recrystallized from ethanol to give the title compound (0.23 g, yield 50%).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9](O)[C@H:8]([O:11][CH2:12][O:13][CH3:14])[CH2:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C1(C)C=CC=CC=1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:45]([N:1]1[C@@H:4]2[C@H:9]1[C@H:8]([O:11][CH2:12][O:13][CH3:14])[CH2:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5]2)(=[O:47])[CH3:46]
Reactant: COCO[C@@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCO[C@@H]1CC(C(=O)OC)=C[C@H]2[C@@H]1N2C(C)=O
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a solution of azido alcohol 15 (150 mg, 0.58 mmol) in toluene (5 mL) was added triphenylphosphine (152 mg, 0.58 mmol) and the reaction mixture was refluxed for 3 h at 110° C. After removal of the solvent under reduced pressure, diethylether (1 mL) was added, and the mixture cooled with ice-bath. The precipitated triphenylphosphine oxide was removed by filtration and the filtrate evaporated. This procedure was repeated to remove any traces of triphenylphosphine oxide. The residue obtained was then dissolved in dry CH2Cl2 (20 mL) cooled at 0° C. To this solution was added Et3N (175.74 mg, 1.74 mmol), DMAP (4-Dimethylamine pyridine) (5 mg) and acetic anhydride (118.32 mg, 1.16 mmol) and the mixture stirred at 25° C. for further 45 minutes. After completion of reaction (monitored by TLC), the reaction mixture was quenched by addition of H2O (10 mL). The organic layer was separated, washed with brine, dried (Na2SO4) and subjected to column chromatographic purification with petroleum ether/ethyl acetate (7:3 v/v) to afford the cyclic acetamide aziridine 16.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[CH:25]1([C:28]([Cl:30])=[O:29])[CH2:27][CH2:26]1>CC1C=CC=CC=1>[ClH:30].[CH3:1][O:2][CH2:3][C:4]1([N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: COCC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: Cc1ccccc1
Product: COCC1(N(C(=O)C2CC2)c2ccccc2)CCN(CCc2ccccc2)CC1
Product: Cl

Procedure:
To a stirred mixture of 3.25 parts of 4-(methoxymethyl)-N-phenyl-1-(2-phenylethyl)-4-piperidinamine and 36 parts of dry methylbenzene is added a mixture of 1.25 parts of cyclopropanecarbonyl chloride and 9 parts of dry methylbenzene at room temperature. The whole is stirred and refluxed for 3 hours. The reaction mixture is filtered hot and upon cooling, the product is allowed to crystallize from the filtrate. It is filtered off, washed with 2,2'-oxybispropane and dried, yielding N-[4-(methoxymethyl)-1-(2-phenylethyl)-4-piperidinyl]-N-phenylcyclopropanecarboxamide hydrochloride; mp. 178.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Br[CH:13]([CH:20]=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClCCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CCOC(=O)CC(Br)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cnc(-c2ccc(OC)cc2)s1
Yield: 66.5 %

Procedure:
4-Methoxythiobenzamide (1.62 g, 9.7 mmol) and ethyl 3-bromo-4-oxobutanoate (2.02 g, 9.7 mmol) were suspended in 1,2-dichloroethane (25 ml), and the mixture was heated under reflux for 3 hours. The reaction mixture was diluted with ethyl acetate, successively washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give ethyl [2-(4-methoxyphenyl)-1,3-thiazol-5-yl]acetate (1.79 g, yield: 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10]Br>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Br:10])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 91.3 %

Procedure:
306 g of 2-fluoroanisole was dissolved in 750 ml of chloroform. To the resulting solution, was added dropwise 389 g of bromine under stirring at room temperature. After the completion of the addition, the reaction mixture was heated under reflux for nine hours and then allowed to cool to room temperature. The mixture was washed with 500 ml of a 5% aqueous solution of sodium hydroxide and then the organic layer was washed with 500 ml portions of water thrice. The organic layer was separated and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by distillation (main fraction: 14 mmHg, 98°-100° C.) to thereby give 454 g of 2-fluoro-4-bromoanisole. Yield: 91%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COc1ccc(Nc2ccc(F)cc2)cc1
Temperature: 110 °C
Yield: 96.2 %

Procedure:
Following general procedure E, a mixture of 4-chloroanisole (123 μL, 1.0 mmol), 4-fluoroaniline (114 μL, 1.2 mmol), NaOt-Bu (115 mg, 1.2 mmol), 10 (0.08 mg, 0.01 mol %), 1 (0.05 mg, 0.01 mol %), and Bu2O (1 mL) was heated to 110° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (209 mg, 94%), mp 59-60° C. 1H NMR (300 MHz, CDCl3) δ: 7.03-6.86 (m, 8H), 5.41 (s, 1H), 3.81 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 159.0, 155.8, 155.2, 141.4, 136.8, 121.4, 118.0, 117.9, 116.2, 115.9, 115.0, 55.8 ppm. IR (neat, cm−1): 3391, 3007, 1508, 1314, 1243, 1221, 1027, 814, 772, 591. Anal. Calcd. for C13H12FNO: C, 71.87; H, 5.57. Found: C, 71.89; H, 5.62.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:11]OS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(O)C.ClCCl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][N:11]=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Brc1ccc2oncc2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-bromo-2-hydroxy-benzaldehyde (2.0 g, 10 mmol) in ethanol (10 mL) at room temperature was treated with hydroxylamine-O-sulfonic acid (1.69 g, 15 mmol), stirred for 20 minutes, diluted with dichloromethane (50 mL), cooled to 0° C. and treated with a solution of sodium bicarbonate (3 g) in water (25 mL). The solution was stirred at 0° C. for 30 minutes. The organic layer was removed and the aqueous layer was extracted with dichloromethane. The aqueous layer was treated with additional dichloromethane (50 mL) and stirring was continued for one hour. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The concentrate was recrystallized from ethanol to give 970 mg (49%) yield of the desired product. MS (ESI(−)) m/e 195.9, 197.9 (M−H)−.
Reaction SMILES: [CH3:1][I:2].[C:3]([NH:6][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][O:10][N:11]=1)(=[O:5])[CH3:4]>CC(C)=O>[I-:2].[C:3]([NH:6][C:7]1[C:8]([C:12]2[CH:13]=[N+:14]([CH3:1])[CH:15]=[CH:16][CH:17]=2)=[N:9][O:10][N:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1nonc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CC(=O)Nc1nonc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl iodide (450 μl, 7.2 mmol) was added to a solution of 3-(4-acetylamino-1,2,5-oxadiazol-3-yl)pyridine (490 mg, 2.4 mmol) in acetone. The reaction mixture was stirred at room temperature for 18 h and the precipitate collected by filtration. Yield: 640 mg (77%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.C([O-])(=O)C.[Na+].[I:26]Cl>C(O)(=O)C>[I:26][C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=3)[CH:7]=[C:2]([CH3:1])[C:3]2=[N:20][CH:19]=1
Reactant: ClI
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Temperature: 23 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a solution of 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20 step 2) (5.0 g, 18 mmol) in 50 mL of acetic acid was added sodium acetate (1.68 g, 20 mmol) and a solution of iodine monochloride (2M, 10.3 mL, 20.6 mmol)—slightly exothermic. The reaction mixture was stirred at 23° C. for 16 h, then partitioned between 300 mL of water and 300 mL of EtOAc. The organic layer was washed with sat. NaHCO3, water, aq. sodium sulfite, water, then dried over Na2SO4, filtered and concentrated to give the title compound as an off-white solid (6.47 g, 89%). MS (ISP) 403.3 [(M+H)+].
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)C.[N:24]#[C:25]Br>C(Cl)Cl.C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:14]([N:13]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:25]#[N:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a dry 2 L round bottom flask, equipped with an overhead stirrer, charged: sodium acetate (120 gm), 1 dibenzyl amine (100 gm) and 600 mL of ethanol. To this suspension at room temperature, was added a 3 M solution of cyanogen bromide in methylene chloride over 30 minutes (340 mL). The suspension was allowed to stir at ambient temperature until reaction completion was observed via HPLC. The reaction mixture was diluted with 1 L of toluene and 1 N sodium hydroxide was added over 15 minutes. The reaction mixture was stirred for 1 hour and the layers separated. The organic layer was dried over sodium sulfate, filtered, and concentrated to an oil that solidified upon standing. Recrystallization from a 1:1 2 L mixture of IPE/Heptanes gave 101 g (89%) of product. 1H NMR (400 MHz, CD3OD) 7.42-7.15 (m, 10H), 1.31 (s, 4H). 13C NMR (400 MHz, CD3OD) δ 135.1, 128.8, 128.7, 128.5, 118.0, 54.6. C, H, N Calculated (found) 81.05 (80.71), 6.35 (6.52), 12.60 (12.65)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH2:7]([O:9][C:10](Cl)=[O:11])[CH3:8].[N+:13]([O-])([OH:15])=[O:14]>C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[N:4]=[C:3]1[C:10]([O:9][CH2:7][CH3:8])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Cl
Reactant: Cn1ccnc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1C

Procedure:
Ethyl 1-methyl-4-nitroimidazole-2-carboxylate (10) was prepared by treatment of N-methylimidazole (16) with ethylchloroformate and triethylamine followed by nitration with nitric acid. ##STR19##
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Cu](C#N)[C:28]#[N:29]>CN(C)C=O.[Cl-].[NH4+].[OH-].[NH4+]>[C:28]([C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1)#[N:29]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Reactant: N#C[Cu]C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OC2)c1ccc(F)cc1F
Yield: 79.3 %

Procedure:
A solution of 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp (33.7 mg, 0.0772 mmol, 1 equiv) and copper cyanide (22 mg, 0.24 mmol, 3.2 equiv) in N,N-dimethylformamide (1 mL) was heated at 250° C. in the microwave for 30 min. The reaction mixture was diluted with 9:1 saturated aqueous ammonium chloride solution/ammonium hydroxide (10 mL). The resulting mixture was extracted with dichloromethane (3×5 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (11:4/hexanes:ethylacetate) provided 161bp as a white solid (23.4 mg, 79%). 1H NMR (500 MHz, CDCl3) δ 7.40-7.42 (m, 2 H), 7.32 (m, 1 H), 6.99 (t, J=8.1 Hz, 1 H), 6.92 (m, 1 H), 6.88 (s, 1 H), 5.23 (s, 2 H), 3.40 (s, 3 H). LCMS (ESI) m/z: 383.1