Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[NH:14][C:13]2=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:25](I)[CH3:26]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[N:14]([CH2:25][CH3:26])[C:13]2=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(C)cc3c2=O)CC1
Product: CCOC(=O)N1CCC(n2c(=O)c3cc(C)ccc3n(CC)c2=O)CC1
Yield: 79 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 1.0 g (3.02 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound f) was used in place of Compound 24 and ethyl iodide was used in place of methyl iodide, whereby 855.0 mg (yield: 79%) of Compound b was obtained as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10](=[O:24])[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:8]=2[N:7]=[CH:6]1.[I-:25].[Na+]>C(#N)C>[I:25][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10](=[O:24])[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:8]=2[N:7]=[CH:6]1
Reactant: [I-]
Reactant: O=c1c2c(ncn2CCCCl)c2cccnc2n1-c1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: O=c1c2c(ncn2CCCI)c2cccnc2n1-c1ccccc1
Yield: 71.5 %

Procedure:
To 200 ml of acetonitrile were added 18 g (0.052 mol) of Compound 68 obtained in Example 68 and 12 g (0.078 mol) of sodium iodide, and the mixture was refluxed for 24 hours. In the course of refluxing, 7.8 g (0.052 mol) of sodium iodide was added to the mixture. After cooling, the solvent was evaporated under reduced pressure and water was added to the residue. Then, extraction was carried out with chloroform, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a crude product. Recrystallization from ethyl acetate-n-hexane gave 16 g (yield 73%) of Compound 69.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:20](=[O:30])[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][CH3:23].O>C1COCC1>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:30])[CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH3:23])=[CH:3][CH:4]=1
Reactant: COCOc1ccc(Br)cc1
Reactant: CCC(C(=O)N(C)OC)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(C(=O)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a stirred solution of 13 (99.0 g, 0.46 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 310 mL, 0.50 mol) dropwise at −78° C. The reaction mixture was stirred for 30 min and 14 (90.1 g, 0.43 mol) dissolved in THF (500 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h and then slowly warmed to 0° C. H2O (500 mL) was added and the volatiles were removed under reduced pressure. The residue was extracted with Et2O (3×500 mL) and the combined extracts were washed with water (500 mL) and brine (500 mL). The mixture was dried over MgSO4 and concentrated. The residue was recrystallized from hexanes to afford 97.6 g (80%) of 15 as white needles. 1HNMR (400 MHz, DMSO-d6): δ 0.79 (t, J=7.3 Hz, 3H), 1.68 (h, J=7.0 Hz, 1H), 2.03 (h, J=7.0 Hz, 1H), 3.32 (s, 3H), 4.65 (t, J=7.3 Hz, 1H), 5.21 (s, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.15 (t, J=7.1 Hz, 1H), 7.23-7.30 (m, 4H), 7.98 (d, J=8.8 Hz, 2H).
Reaction SMILES: C([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[Cl-].[OH:21][NH3+].[N:23]1[CH:28]=CC=CC=1>C(O)C>[OH:21][N:23]=[CH:28][N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:17])[CH3:18])[NH:11][C:12](=[O:14])[CH3:13]
Reactant: c1ccncc1
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Product: CCCCCN(C=NO)C(=O)[C@H](CC(C)C)NC(C)=O

Procedure:
In 30 ml of ethanol was dissolved 750 mg of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 210 mg of hydroxyammonium chloride and 5 ml of pyridine were added thereto. The mixture was allowed to react at room temperature for 24 hours. After completion of the reaction, the reaction mixture was washed with a saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by mediumpressure column chromatography on silica gel to obtain 600 mg of the titled compound as a colorless crystal.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C(=N[NH:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([C:35](=[O:42])[N:36]([CH:38]3[CH2:41][CH2:40][CH2:39]3)[CH3:37])[CH:29]=2)=[C:22]([CH3:43])[CH:21]=1)C)C.C([O-])(O)=O.[Na+].[CH3:50][CH2:51][O:52][C:53]([CH3:55])=[O:54]>C1(C)C=CC=CC=1>[CH2:51]([O:52][C:53]([C:55]1[NH:19][C:20]2[C:21]([CH:1]=1)=[C:22]([CH3:43])[C:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([C:35](=[O:42])[N:36]([CH:38]3[CH2:41][CH2:40][CH2:39]3)[CH3:37])[CH:29]=1)=[C:24]([CH3:26])[CH:25]=2)=[O:54])[CH3:50]
Reactant: CCOC(=O)C(C)=NNc1cc(C)c(Oc2ccc(O)c(C(=O)N(C)C3CCC3)c2)c(C)c1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(=O)N(C)C4CCC4)c3)c(C)cc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of p-toluenesulfonic acid (163 mg, 0.86 mmol) and 2-({4-[3-(Cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-hydrazono)-propionic acid ethyl ester (259 mg, 0.57 mmol) in toluene (2 mL) was heated to reflux. After vigorously stirring at reflux for 1 hour, the reaction mixture was then allowed to cool to room temperature. To which was added saturated aqueous NaHCO3 (15 mL) and EtOAc (20 mL). The EtOAc layer was separated, washed with saturated NaHCO3 (2 times 25 mL), brine (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (4% MeOH in CH2Cl2) to afford the title compound (136 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ9.45 (s, 1H), 8.89 (br s, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 7.04 (dd, 1H), 6.97 (d, 1H), 6.42 (d, 1H), 4.46-4.38 (m, 3H), 2.93 (s, 3H), 2.36 (s, 3H), 2.26 (s, 3H), 2.22-2.01 (m, 2H), 1.74-1.54 (m, 2H), 1.43 (t, 3H), 1.36-1.20 (m, 2H). MS (APCI+) Calc: 436.2, Found: 437.3 (M+1).
Reaction SMILES: C(Cl)Cl.[C:4](Cl)(=[O:8])[C:5]([CH3:7])=[CH2:6].[CH2:10]([N:17]([CH2:24][CH2:25][OH:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C>[CH2:10]([N:17]([CH2:24][CH2:25][O:26][C:4](=[O:8])[C:5]([CH3:7])=[CH2:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCCN(Cc1ccccc1)c1ccccc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCN(Cc1ccccc1)c1ccccc1

Procedure:
1000 ml of dried methylene chloride are placed in a 4 l sulfonating vessel at 0° C. together with 334 g of methacrylic acid chloride. A mixture of 500 ml of dried methylene chloride, 323 of dried triethylamine and 454 of N-benzyl-N(β-hydroxyethyl)aniline, (the compound of formula 1a) are added drop by drop to this mixture at 0°-10° C. The reaction mixture is allowed to rise to room temperature slowly and is controlled on a thin layer chromatograph (silica gel) solvent: toluene/acetic acid ester 2:1. After the end of the reaction (after standing overnight), the reaction mixture is filtered and washed three times with one liter of a 10% aqueous NaOH solution and finally four times each time with 1 l of water. The organic phase is then dried over sodium sulphate and the solvent is removed in a rotary evaporator. 482 g of the product of formula 1d ##STR15## results.
Reaction SMILES: [Li+].[CH2:2]([O:4][P:5]([CH2:10][S:11]([O-:14])(=[O:13])=[O:12])([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].C([Li:19])CCC.[C:20](#[N:23])[CH:21]=[CH2:22].O>O1CCCC1.C(O)(=O)C>[Li+:19].[C:20]([CH2:21][CH2:22][CH:10]([P:5]([O:7][CH2:8][CH3:9])([O:4][CH2:2][CH3:3])=[O:6])[S:11]([O-:14])(=[O:13])=[O:12])#[N:23]
Reactant: [Li]CCCC
Reactant: C=CC#N
Reactant: CCOP(=O)(CS(=O)(=O)[O-])OCC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C(CCC#N)S(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 2.38 g (0.01 mole) of diethoxyphosphinylmethanesulfonate lithium salt (Carretero, et al.; Tetrahedron, 43, 5125 (1987)) in 50 ml of anhydrous tetrahydrofuran is stirred in a -40° bath under a dry nitrogen atmosphere. To this is added n-butyl lithium (4.4 ml of 2.5M solution in hexanes; 0.011 mole) via syringe over 5 minutes. The reaction mixture is allowed to warm to -15° and is stirred at this temperature for about one hour. To it is then added rapidly a solution of 0.53 g (0.01 mole) of acrylonitrile in 3 ml of anhydrous THF. The reaction mixture is stirred for 1 hour at -15° , and is then allowed to warm to room temperature over several hours as the bath warms up. It is stirred at ambient temperature for several hours, and then is quenched by addition of 50 ml of water containing 0.6 g (0.01 mole) of acetic acid. The reaction mixture is concentrated under vacuum on a rotary evaporator to get rid of the THF, and the aqueous layer is extracted with ether to remove some impurities. The water layer is evaporated to dryness under vacuum, and the resulting residue is purified by flash chromatography on silica gel using chloroform/methanol as eluant, to afford 3-cyano-1-diethoxyphosphinylpropanesulfonic acid lithium salt.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[Br:22].[C:23](=[O:25])=[O:24]>C1COCC1.CCOCC>[Br:22][C:15]1[C:14]([F:13])=[C:19]([C:18]([F:20])=[C:17]([F:21])[CH:16]=1)[C:23]([OH:25])=[O:24]
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1c(F)c(F)cc(Br)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
n-Butyl lithium (2.6M in hexanes, 32 ml, 84 mmol) was added over 10 minutes to a solution of diisopropylamine (8.89 g, 88 mmol) in THF (80 ml) stirred under N2 at 0° C. After a further 10 minutes at 0°, the solution was transferred by catheter over 40 minutes to a solution of 2,4,5-trifluorobromobenzene (16.88 g, 80 mmol) in THF (200 ml) stirred under N2 at -78° C. After a further 15 minutes the solution was blown through a catheter over ~2 minutes onto a slurry of CO2 (~200 ml) in ether (400 ml) with vigorous stirring. When the CO2 evaporated the slurry was washed with dilute HCl (1M, 200 ml) and water (100 ml). The organic phase was extracted with dilute NaOH (0.5M, 2×100 ml). The aqueous phase was extracted with ether (2×100 ml), and the combined organic phases were washed with water (100 ml), saturated brine (100 ml), and dried (MgSO4). The solvent was removed under reduced pressure to give 3-bromo-2,5,6-trifluorobenzoic acid (17.25 g, 84.5%) as white microcrystalline needles; mp 114°-6° C. (sublimation). EXAMPLE KK
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]2[N:14]=[C:13]3[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:12]3=[N:11]2)[C:4]=1[OH:23].C(N(CC)CC)C.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>C1COCC1>[C:31]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]2[N:14]=[C:13]3[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:12]3=[N:11]2)[C:4]=1[OH:23])(=[O:35])[C:32]([CH3:34])=[CH2:33]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc(CO)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1cc(C)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Temperature: -10 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
In a 100 ml round bottom 3-neck flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 3.58 g (11.1 mmol) 2-(hydroxymethyl)-4-methyl-6-(5-(trifluoromethyl)-2H-benzo[d][1,2,3]triazol-2-yl)phenol in 60 ml anhydrous THF. Triethylamine (5.6 ml, 40 mmol) was added and the mixture was cooled to −10° C. Methacryloyl chloride (1.373 g, 13.1 mmol) was added dropwise and the mixture was stirred for 1 hour at −10° C. followed by 20 hours at ambient temperature. The solid was filtered off and rinsed with diethyl ether and the resultant filtrate was poured into 100 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and recrystallized with diethyl ether to give 1.90 g (44%) of a white solid. 1H NMR (CDCl3) delta: 11.17 (s, 1H, Ar—OH), 8.29 (s, 1H, Ar—H benzotriazole 4-position), 8.21 (s, 1H, Ar—H phenol 6-position), 8.06 (d, 1H, Ar—H benzotriazole 6-position), 7.69 (d, 1H, Ar—H benzotriazole 7-position), 7.29 (s, 1H, Ar—H phenol 4-position), 6.20 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.39 (s, 2H, Ar—CH2), 2.42 (s, 3H, Ar—CH3), 2.00 (s, 3H, C═C—CH3).
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([O:13][C:14]([CH:16]([O:23]/[N:24]=[C:25](/[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[S:45][CH:46]=1)\[C:26]([O:28]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].FC(F)(F)C(O)=O>C(Cl)Cl>[C:9]([O:13][C:14]([CH:16]([O:23]/[N:24]=[C:25](/[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[S:45][CH:46]=1)\[C:26]([OH:28])=[O:27])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)C(O/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1ccccc1
Temperature: -30 °C
Yield: 56.2 %

Procedure:
To a mixture of 4 ml of methylene dichloride and 1 ml of anisole was added 2.61 g (0.0033 mole) of benzhydryl (Z)-2-(α-tert-butoxycarbonylbenzyloximino)-2-(2-tritylaminothiazol-4-yl)acetate and after cooling the mixture to -30° C., 3 ml of trifluoroacetic acid was added dropwise to the mixture at a temperature below -20° C. over a period of 5 minutes. Thereafter, the mixture was maintained for one hour at -20° C. to -15° C. and then, methylene dichloride and trifluoroacetic acid were distilled off at low temperature under reduced pressure to provide an oily product. The oily product was subjected to silica gel column chromatography, eluted with a mixture of chloroform, isopropyl alcohol, and formic acid (90:10:2), the fractions containing the desired product were collected, and the solvents were distilled off to provide 1.15 g (Z)-(α-tert-butoxycarbonylbenzyloximino)-2-(2-tritylaminothiazol-4-yl)acetic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:32]=[C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:23])[C:20]([OH:33])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:22](=[O:23])[C:21]2[CH:32]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=2[O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Br)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Br)cc3C(=O)Nc3ccc(Cl)cc3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-bromo-4′-chlorosalicylanilide (653 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (59 mg, yield 23%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.[NH2:12][C:13]1[S:14][C:15]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[S:14][C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[O:9])=[CH:5][N:4]=1
Reactant: O=C(O)c1ccc(CCl)nc1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(CCl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
6-(Chloromethyl)nicotinic acid (172 mg, 1.00 mmol) obtained in Step 1, 2-amino-4-(2-furyl)-5-morpholinothiazole (251 mg, 1.00 mmol) obtained in Step 1 of Example 29 and PyBOP (572 mg, 1.10 mmol) were dissolved in DMF (4 mL), and triethylamine (0.307 mL, 2.20 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under the reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:3) to afford the entitled Compound 36 (194 mg, 48%).
Reaction SMILES: [C:1]([NH:6][C:7](=[O:11])OCC)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:1]([NH:6][C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Nc1ccccc1
Reactant: C=C(C)C(=O)NC(=O)OCC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NC(=O)Nc1ccccc1
Temperature: 120 °C
Yield: 45.5 %

Procedure:
A reaction vessel was charged with 78.5 g of ethyl N-methacryloylcarbamate and 46.5 g of aniline to which 100 g of toluene were added and heated at 120° C. for 30 minutes. The resulting mixture was condensed under reduced pressure and isolated by column chromatography to obtain 46.4 g of N-methacryloyl-N'-phenyl urea having a melting point of 165° to 166° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N+:16]([O-])=O)[CH:8]=1)#[CH:2]>[OH-].[NH4+].O1CCCC1.[Zn]>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:16])[CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C#Cc1cccc(Oc2ccc(N)c(N)c2)c1
Reaction time: 0.5 h

Procedure:
To a rapidly stirred suspension of 25 g (0.38 g atom) of powdered zinc in 25 ml of concentrated ammonium hydroxide was added a solution containing 5.0 g (17.6 mmoles) of 4-(3-ethynylphenoxy)-o-dinitrobenzene dissolved in 25 ml of tetrahydrofuran. The mixture was stirred at room temperature for 1/2 hour, at which time an additional 5 ml of ammonium hydroxide was added, and the solution stirred an additional half hour. At that time, the reaction mixture was filtered by suction, and the residue was washed with several portions of tetrahydrofuran. The filtrate was extracted with several portions of ether, and the combined ether extracts washed with water. Evaporation of the organic layer in vacuo yielded a dark red oil. Chromatography of the residue on 1" × 12" dry column of silica gel afforded an initial red band (elution with methylene chloride) of side-product. Further elution using ethyl acetate produced a second band of desired product. Evaporation of solvent in vacuo yielded 3.3 g (84%) of 4-(3-ethynylphenoxy)-o-phenylenediamine as a dark orange oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[C:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:8]=[CH:9][N:4]2[C:3]=1[CH2:16][O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20].C([Mg]Br)C.CN(OC)[C:31](=[O:34])[CH2:32][CH3:33].[Cl-].[NH4+]>O1CCCC1>[C:31]([C:2]1[S:6][C:5]2=[C:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:8]=[CH:9][N:4]2[C:3]=1[CH2:16][O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)N(C)OC
Reactant: CC[Si](CC)(CC)OCc1c(Br)sc2c(-c3cccnc3)ncn12
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)c1sc2c(-c3cccnc3)ncn2c1CO[Si](CC)(CC)CC
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A solution of 5.14 g of 2-bromo-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole in 36 ml of tetrahydrofuran under an argon atmosphere was cooled to −60° C., 13.3 ml of a 0.89 M tetrahydrofuran solution of ethylmagnesium bromide was added thereto, and the mixture was stirred for one hr. N-Methyl-N-methoxypropionamide (1.71 g) was added thereto at −30° C., and the mixture was stirred at room temperature for 12 hr. A 20% aqueous ammonium chloride solution was added to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order and was then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by column chromatography on silica gel (3 to 6% methanol/methylene chloride) to give 3.88 g of 2-propionyl-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](=[O:20])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.Br.O.C(=O)([O-])[OH:24].[Na+]>CS(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](=[O:20])[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:24])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: O=C([O-])O
Reactant: Cc1cccc(CC(=O)c2ccc3nnn(C)c3c2)n1
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(C(=O)C(=O)c2ccc3nnn(C)c3c2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of 1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethanone (280 mg, 1.05 mmol) in 16 ml dimethyl sulfoxide was heated to 60° C. 48% hydrobromic acid solution in water (7.4 ml, 65.1 mmol) was slowly added over several minutes. Once the addition was complete, the reaction was stirred at 60° C. for 3 hours. The reaction was cooled to room temperature and poured into 75 ml water. The pH was adjusted to 8 with the addition of saturated sodium hydrogen carbonate solution. The aqueous layer was then extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to afford 1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethane-1,2-dione (146 mg, 50%).