Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:22])[CH:3]=1>Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Agent: Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Yield: 97.6 %

Procedure:
A suspension of 4-(4′-bromo-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (2.94 g, 0.00805 mol) in 6 M hydrochloric acid was refluxed for 23 hours and allowed to cool. The solids were filtered, washed with 0.1 M hydrochloric acid, and dried under house vacuum to give 2.76 g of 4-(4′-bromo-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid as a pale yellow solid; mp 145-147° C.
Reaction SMILES: C[O-].[Na+].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:13]([O:12][C:4](=[O:11])[CH:5]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Yield: 66.6 %

Procedure:
In 200 ml of ethanol, 16.2 g of sodium methoxide were dissolved. Into this solution, 49.5 g of diethyl malonate were dropped and gently refluxed. 37.98 g of benzyl chloride were dropped into the mixture over one hour and the mixture was refluxed for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and water was added to the residue. After extraction with ethyl acetate, the ethyl acetate was dried with sodium sulfate anhydride. After removing the solvent under reduced pressure, followed by purification with distillation, 50 g of 2-benzylmalonic acid diethyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.O>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (400 mg) in N,N-dimethylformamide (2.6 mL) was added cesium carbonate (957 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added (3-bromopropoxy)(tert-butyl)dimethylsilane (979 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (630 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH2:20])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[S:27](=[N:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])=[O:28]>[2H]C(Cl)(Cl)Cl>[S:27](=[N:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:20][C:4]1[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:34])=[O:28]
Reactant: O=S=Nc1cccc(C(=O)Cl)c1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [2H]C(Cl)(Cl)Cl
Agent: [K+]
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N=S=O)c1
Temperature: 25 °C

Procedure:
To a suspension of 2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (0.082 g, 0.27 mmol) (prepared according to EP 1,006,102) and finely ground potassium carbonate (0.112 g, 0.81 mmol) in deuterochloroform (1.0 ml) under stirring at 25° C., was added 3-sulfinylamino-benzoyl chloride (0.055 g, 0.27 mmol) (Example 1.1) dissolved in dry deuterochloroform (1.0 ml). The reaction mixture was stirred at 40° C. for 16 hours. A sample of the supernatant was submitted to 1H-NMR spectroscopy. The desired compound was detected in the reaction mixture, based on its characteristic signals (see 1H-NMR spectral data as described in Example 2.2), together with unreacted starting materials. An aliquot of the reaction mixture was diluted in dry acetonitrile and was submitted to mass spectrometry via direct injection (same conditions as described in Example 2.1). Calculated exact mass: 468; [M-H]− observed: 467.00.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH:31]=[O:32])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH:30]2[C:31](=[O:32])[O:13][C:12]3[NH:11][C:10]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[F:21])=[N:9][C:8]=3[CH:1]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: O=C/C=C/c1ccc(Cl)cc1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccc(Cl)cc1
Yield: 58 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(4-chlorophenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 12 as a white solid (78 mg, 58%). Analytical data for 12: 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J=7.9 Hz, 1H), 7.89 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.31-7.26 (m, 3H), 7.12-6.92 (m, 6H), 4.08 (d, J=6.8 Hz, 1H), 3.56 (ddd, J=9.8, 6.9, 4.9 Hz, 1H), 3.29 (dd, J=14.9, 5.0 Hz, 1H), 2.43 (dd, J=14.9, 9.8 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.7, 159.11 (d, JCF=244.0 Hz), 155.38 (d, JCF=242.2 Hz), 148.9, 136.8, 136.5, 136.3, 132.6, 130.4, 129.3, 128.8, 128.4, 127.9, 118.32 (dd, JCF=12.4, 9.3 Hz), 117.12 (dd, JCF=25.5, 8.6 Hz), 116.64 (dd, JCF=24.8, 9.2 Hz), 114.51 (dd, JCF=26.9, 3.7 Hz), 110.69 (d, JCF=3.8 Hz), 47.2, 38.6, 32.3; IR (film) cm−1 1769, 1638, 1492, 1481, 1462, 1239, 1171, 1118, 1096, 1032, 813, 766, 741, 699; LRMS (ESI): Mass calcd for [M+H]+ C25H18ClF2N2O2: 451.1. found 451.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (major)=40.5, Rt2 (minor)=50.6 min; er=98:2.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[NH:13]1C=CN=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.S([O-])([O-])(=O)=S.[Na+].[Na+].[C-]#N.[Na+]>C1(C)C=CC=CC=1.C(#N)C>[C:14]([CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)#[N:13]
Reactant: c1c[nH]cn1
Reactant: OCC1CCc2ccccc2N1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [C-]#N
Solvent: CC#N
Solvent: Cc1ccccc1
Product: N#CCC1CCc2ccccc2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of 2-hydroxymethyltetrahydroquinoline (35.9 g, 0.22 mol), imidazole (35.95 g, 0.528 mol), and triphenylphosphine (69.24 g, 0.264 mol) in a mixed solvent of 5:1 toluene/acetonitrile (750 mL) was added iodine (61.42 g, 0.242 mol) at 0° C. The mixture was stirred for 15 min at 0° C. and for 30 min at room temperature. Aqueous sodium thiosulfate solution (200 mL) was added. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The residue was triturated with diethyl ether and the insoluble materials were removed by filtration. The filtrate was concentrated and the residual oil was dissolved in DMF (200 mL). To the solution was added sodium cyanide (43.2 g, 0.881 mol) and the mixture was heated at 80° C. for 10 h. The resulting mixture was poured into ice-water and extracted with a mixture of toluene and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 1:1 hexane/dichloromethane to 100% dichloromethane as eluents to give 31.6 g of the title compound (94%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([C:17]#[C:18][CH:19]([OH:22])[CH2:20][CH3:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([C:17]#[C:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(O)C#Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)C#Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of oxalyl chloride (0.168 mL, 1.92 mmol) in dichloromethane (2.5 mL) at −78° C. was added dimethylsulfoxide (0.231 mL, 3.26 mmol) dropwise followed by 1-phenylpent-1-yn-3-ol (61.4 mg, 0.383 mmol) in 0.5 mL of dichloromethane dropwise. The reaction mixture was stirred at −78° C. for 1 h., and triethylamine (0.534 mL, 3.83 mmol) was then added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (2.5 mL), washed with water (1 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (10/1) afforded 1-phenylpent-1-yn-3-one (37 mg). The compound had an HPLC ret. time=2.88 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=159+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11](=O)[CH3:12])=[C:9]2[C:4]([N:5]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[CH2:6][CH2:7][CH2:8]2)=[N:3]1.Cl.[O:24]([NH2:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:25][O:24][N:26]=[C:11]([C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][N:5]2[C:14]1[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])[CH3:12]
Reactant: CC(=O)c1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=C(C)c1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2
Temperature: 75 °C
Yield: 45.7 %

Procedure:
A mixture of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-yl]ethanone (20 mg, 0.067 mmol), methoxylamine hydrochloride (12 mg, 0.148 mmol), and pulverized potassium carbonate (39 mg, 0.26 mmol) in 2 mL of 95% ethanol was heated at 75° C. under an atmosphere of nitrogen for 1 hr. The solvent was evaporated, the residue was treated with 50 ml of ethyl acetate, washed with brine, dried over magnesium sulfate, and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with acetone/hexane (4:96) affording 10 mg (47% yield) of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazol[3,4-b]pyridine-3-yl]ethanone O-methyl-oxime (6-4) as a brown oil: ms (M+H)+=327.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=2)=[CH:10][C:9](Br)=[CH:8][CH:7]=3)[CH:3]=1.[C:37]1([C:43]2[N:47]([C:48]3[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=3)[C:46]3[CH:57]=[CH:58][CH:59]=[CH:60][C:45]=3[N:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:37]1([C:43]2[N:47]([C:48]3[CH:53]=[CH:52][C:51]([C:2]4[CH:15]=[CH:14][C:13]5[C:4](=[C:5]([C:27]6[CH:36]=[CH:35][C:34]7[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=7)[CH:28]=6)[C:6]6[C:11]([C:12]=5[C:16]5[CH:25]=[CH:24][C:23]7[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=7)[CH:17]=5)=[CH:10][C:9]([C:51]5[CH:50]=[CH:49][C:48]([N:47]7[C:46]8[CH:57]=[CH:58][CH:59]=[CH:60][C:45]=8[N:44]=[C:43]7[C:37]7[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=7)=[CH:53][CH:52]=5)=[CH:8][CH:7]=6)[CH:3]=4)=[CH:50][CH:49]=3)[C:46]3[CH:57]=[CH:58][CH:59]=[CH:60][C:45]=3[N:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OB(O)c1ccc(-n2c(-c3ccccc3)nc3ccccc32)cc1
Reactant: Brc1ccc2c(-c3ccc4ccccc4c3)c3cc(Br)ccc3c(-c3ccc4ccccc4c3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2nc3ccccc3n2-c2ccc(-c3ccc4c(-c5ccc6ccccc6c5)c5cc(-c6ccc(-n7c(-c8ccccc8)nc8ccccc87)cc6)ccc5c(-c5ccc6ccccc6c5)c4c3)cc2)cc1
Yield: 73 %

Procedure:
2.0 g (3.4 mmol) of 2,6-dibromo-9,10-di(2-naphthyl)anthracene, 2.4 g (7.5 mmol) of 4-(2-phenyl-1H-benzimidazol-1-yl)phenylboronic acid, and 0.16 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 30 mL of 1,2-dimethoxyethane. Then, 15 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. The resultant was stood to cool. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 2.4 g of a greenish white solid (73% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 966 with respect to a molecular weight of 966.37.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[NH:2]2.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:2]1[C:3](=[O:9])[CH:4]2[CH2:7][CH2:8][CH:1]1[CH2:6][CH2:5]2
Reactant: O=C1NC2CCC1CC2
Reactant: Clc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1C2CCC(CC2)N1c1ccccn1
Temperature: 125 °C
Yield: 61.8 %

Procedure:
A mixture of 2-azabicyclo[2.2.2]octan-3-one (0.6 g, 4.8 mmol), 2-chloropyridine (0.65 g, 5.76 mmol), Cs2CO3 (2.36 g, 7.20 mmol) and xantphos (0.22 g, 0.38 mmol) in 1,4-dioxane (30 ml) was purged with argon gas for 15 min. Tetrakis(triphenylphosphine)palladium (0) (0.22 g, 0.19 mmol) was added and continued purging for another 10 min. The reaction mixture was heated at 125° C. for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and dried under reduced pressure to afford the crude compound. Purification by column chromatography over neutral alumina using 15% ethyl acetate in petroleum ether as eluent afforded 600 mg (61.9%) of 2-(pyridin-2-yl)-2-aza-bicyclo[2.2.2]octan-3-one as pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CSCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-Fluoronitrobenzene (3.0 g, 21.3 mmol) was dissolved in toluene (25 mL). Thiomorpholine (2.4 mL, 23.4 mmol) was added and the mixture stirred overnight at 100° C. At 17 h, the mixture was distributed between ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([C:13]([OH:15])=O)=[CH:5][CH:4]=[C:3]3[CH2:2]1.C1C2=C3C(=CC=C2)C(C(Cl)=O)=CC=C3C1.[CH3:31][O:32][CH2:33][CH2:34][N:35]1[C:39]([CH3:40])=[C:38]([CH3:41])[S:37][C:36]1=[NH:42].CCN(CC)CC>S(Cl)(Cl)=O.C1COCC1>[CH3:31][O:32][CH2:33][CH2:34][N:35]1[C:39]([CH3:40])=[C:38]([CH3:41])[S:37]/[C:36]/1=[N:42]\[C:13]([C:6]1[C:7]2[C:12]3[C:3]([CH2:2][CH2:1][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:5]=1)=[O:15]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(O)c1ccc2c3c(cccc13)CC2
Agent: O=C(Cl)c1ccc2c3c(cccc13)CC2
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccc2c3c(cccc13)CC2
Yield: 21.8 %

Procedure:
The acenaphthene-5-carboxylic acid (Aldrich, 0.29 g, 1.4 mmol) in 5 mL of thionyl chloride was converted to acenaphthene-5-carbonyl chloride using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and acenaphthene-5-carbonyl chloride in 30 mL THF were processed as in Example 134B to afford the title compound (87 mg, 0.24 mmol, 22% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.28 (d, J=0.7 Hz, 3H), 2.33 (d, J=0.7 Hz, 3H), 3.33 (s, 3H), 3.42 (s, 4H), 3.84 (t, J=5.3 Hz, 2H), 4.51 (t, J=5.3 Hz, 2H), 7.30-7.36 (m, 2H), 7.52 (dd, J=8.6, 7.0 Hz, 1H), 8.43 (d, J=7.5 Hz, 1H), 8.81 (d, J=8.8 Hz, 1H); MS (DCI/NH3) m/z 367 (M+H)+; Anal. calculated for C21H22N2O2S: C, 68.82; H, 6.05; N, 7.64. Found: C, 68.63; H, 5.72; N, 7.40.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+].C(O)C>ClCCl>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[CH3:1]
Reactant: BrCCBr
Reactant: Cc1cc(I)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(I)ccc1OCCBr

Procedure:
A mixture of 2-methyl-4-iodophenol (5.00 grams), 1,2-dibromoethane (2.76 mL), sodium hydroxide (1.3 grams) and ethanol (100 mL) was stirred at reflux for 5 hours before being poured into ice. The crude solid was dissolved in dichloromethane and washed with 1N NaOH. The organic layer was evaporated in vacuo to give 2-Bromo-1-(2-methyl-4-iodophenoxy)ethane Compound 21a as a tan solid. 1H NMR (CDCl3) δ 6.54 (d,1H), 4.25 (t, 2H), 3.66 (t, 2H), 2.20 (s, 3H).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: Oc1ccccc1F
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccc2F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To an N,N-dimethylformamide (30.0 mL) solution of 2-fluorophenol (5.43 g, 48.4 mmol) and 4-fluorobenzaldehyde (3.00 g, 24.2 mmol) was added potassium carbonate (10.1 g, 72.5 mmol) under nitrogen atmosphere, which was stirred for 16 hours at 80° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15→1:10) to obtain the title compound (5.20 g, 99.4%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:14](I)=[C:13]([I:16])[N:12]=[C:11]1[CH2:17][O:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].CC[Mg+].[Br-].O.CCOCC>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:16])[N:12]=[C:11]1[CH2:17][O:18][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCc1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COCc1nc(I)cn1CCNC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
A solution of [2-(4,5-diiodo-2-methoxymethyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butylester (3.050 g; 6.015 mmol) in anhydrous THF (30 ml), under nitrogen, was cooled to −40° C., and a solution of 1M EtMgBr in THF (6.02 ml; 6.02 mmol) was then added dropwise over 10 min. After addition, the resulting solution was stirred between −40° C. and −30° C. for 10 min. (conversion=53% according to LC-MS), and additional 1M EtMgBr (3 ml; 3 mmol) was added. Stirring at −40° C. was continued for additional 20 min. (reaction completed). The reaction mixture was then treated with water (2 ml) at −40° C., and was allowed to warm-up to rt. Ether (40 ml) was added, and the resulting solution was washed with water (25 ml) and brine (30 ml). The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=50/1) to give the pure product [2-(4-iodo-2-methoxymethyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow solid (1.645 g; 72%). LC-MS: tR=0.70 min.; [M+H]+=382.29 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:39]=[CH:38][C:30]3[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=3[CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:4]2[N:3]=[C:2]([C:27]3[CH:39]=[CH:38][C:30]4[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=4[CH:28]=3)[CH:7]=[CH:6][CH:5]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(S(=O)(=O)c2cccc(Cl)n2)cc1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COc1ccc(S(=O)(=O)c2cccc(-c3ccc4nc(NC(C)=O)sc4c3)n2)cc1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-(4-methoxyphenylsulfonyl)pyridine (0.300 g, 1.06 mmol) was dissolved in 1,4-dioxane (6 mL) and then N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.4 g, 1 mmol), tetrakis(triphenylphosphine)palladium (0) (0.2 g, 0.1 mmol) and 2M sodium carbonate (1 mL, 2 mmol) were added to it. The flask was fit with a reflux condensor and placed into a pre-heated (95° C.) bath. The mixture was allowed to stir under inert atmosphere overnight. The mixture was allowed to cool to ambient temperature and diluted with DMSO. The crude was filtered and purified by reverse-phase HPLC. This gave N-(6-(6-(4-methoxyphenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 440 (MH+). Calculated exact mass for C21H17N3O4S2: 439. 1H NMR (400 MHz, DMSO-d6): 8.53 (s, 1H), 8.15-8.24 (m, 2H), 8.02 (br s, 4H), 7.70 (d, J=7.53 Hz, 1H), 7.7.19 (d, J=7.53 Hz, 2H), 3.83 (s, 3H), 2.15 (s, 3H).