Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>[OH-].[K+].C(O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Br)cc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 80.2 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.40 g, 1.6 mmol) was reacted with 4-bromobenzaldehyde (0.433 g, 2.3 mmol) in 2 mL of 4% KOH in ethanol to afford 0.543 g (81%) of the title compound as a coarse white solid, mp 152-153° C.: CI-MS m/e 423, 425 (M+);
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@H:3]1[O:8][C:7](=[O:9])[C@@H:6]([CH3:10])[C@@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@@H:6]([C@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: C[C@@H]1C(=O)O[C@H](C(Cl)(Cl)Cl)O[C@@H]1C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@@H](C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TO 1.0 g of (2R, 5S, 6R)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan -4-one obtained by a procedure similar to Example 1-(4) were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol, stirred at room temperature for one hour, and 20 ml of water was added followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate and ether was distilled off, and then the residue was subjected to distillation to obtain 0.4 g of isopropyl (2S, 3R)-2-methyl-3-hydroxybutanoate. ##STR41##
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8](O)=O)[CH:3]=1.[C:11]1([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:19]2[S:18][C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:21][CH:20]=2)[CH:3]=1
Reactant: O=C(O)c1cc(Br)sc1Cl
Reactant: c1ccc(-c2cccs2)cc1
Product: Clc1sc(Br)cc1Cc1ccc(-c2ccccc2)s1

Procedure:
5-Bromo-2-chloro-3-thiophenecarboxylic acid (see Japanese Unexamined Patent Publication No. 10-324632) and 2-phenylthiophene were treated in a manner similar to Reference Example 5 to give the target compound as a colorless solid. APCI-Mass m/Z 367/369 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[NH2:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[SH:18]>>[Cl:17][C:16]1[C:11]2[NH:10][C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]=3[S:18][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Cn1c(=O)cc[nH]c1=O
Reactant: Nc1c(S)cccc1Cl
Product: Cn1c(=O)[nH]c2c(c1=O)Nc1c(Cl)cccc1S2

Procedure:
Employing the procedure of Example 1, parts A and B with 3-methylpyrimidine-2,4(1H,3H)-dione and 2-amino-3-chlorobenzenethiol yielded the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:7]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCc1ccc(O)cc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared as described in General Method 5 using 4.53 g (20 mmol) of 3-(4-hydroxy-phenyl)-1-phenyl-propan-1-one from Example L, 1.64 g (24 mmol) of imidazole, 3.62 g (24 mmol) of t-butyldimethylsilyl chloride and 80 mL of CH2Cl2. The product was carried on crude to the next step (see Example TT).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH:17]=[CH:18][C:19]([OH:21])=O)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(OCC)(OCC)=O.[Cl-].[CH3:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH3+:41])[CH2:37][CH2:36]1.CN(C1C=CC=CN=1)C>C(Cl)Cl.C(N(CC)CC)C>[CH3:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:19]([CH:18]=[CH:17][CH:16]=[CH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([O:22][CH3:23])[CH:11]=2)=[O:21])[CH2:37][CH2:36]1
Reactant: COc1cc(C=CC=CC(=O)O)ccc1OCc1ccccc1
Reactant: C[C@H]1CC[C@H]([NH3+])CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCc1ccccc1

Procedure:
Using 4g of 4-(4-benzyloxy-3-methoxyphenyl)-l,3-butadiene-1-carboxylic acid, 3 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 150 ml of methylene chloride, 2.2 g of trans-4-methylcyclohexylammonium chloride, and 0.5 g of -dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 3.62 g of N-(trans-4-methylcyclohexyl)-4-(4-benzyloxy-3-methoxyphenyl)-1,3-butadiene-l-carboxamide (a compound of the present invention) was obtained as a pale yellowhish brown oil, which had the following physiochemical properties:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:11][S:12]([OH:15])(=O)=[O:13]>O>[Cl:11][S:12]([C:5]1[CH:6]=[C:7]([S:12]([Cl:11])(=[O:15])=[O:13])[CH:8]=[C:2]([C:1]([OH:10])=[O:9])[C:3]=1[OH:4])(=[O:15])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)Cl)cc(S(=O)(=O)Cl)c1O

Procedure:
Salicylic acid (10 g) was added to chlorosulphonic acid (60 ml) during 5 minutes. The mixture was then heated at 130°-140° C. for 90 minutes. After cooling, the mixture was cooled and then added dropwise to an excess of a mixture of ice and water, keeping the temperature below 0° C. The precipitated solid was extracted with dichloromethane, and the organic extract was dried over sodium sulphate, and concentrated in vacuo to a small volume and treated with petroleum ether (b.p. 40°-60° C.). The precipitate was filtered off and recrystallized from a large volume of toluene to give 3,5-bis(chlorosulphonyl)salicylic acid (9.95 g), m.p. 185°-187° C.
Reaction SMILES: Br[C:2]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[C:34]([Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])#[CH:35].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH:30]1([N:27]2[CH2:26][CH2:25][N:24]([C:23]3[C:2]([C:35]#[C:34][Si:36]([CH:37]([CH3:39])[CH3:38])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])=[CH:3][C:4]4[C:16](=[O:17])[C:15]5[C:14]6[C:9](=[CH:10][C:11]([C:18]#[N:19])=[CH:12][CH:13]=6)[NH:8][C:7]=5[C:6]([CH3:21])([CH3:20])[C:5]=4[CH:22]=3)[CH2:29][CH2:28]2)[CH2:33][CH2:32][CH2:31]1
Reactant: CC1(C)c2cc(N3CCN(C4CCC4)CC3)c(Br)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)[Si](C#Cc1cc2c(cc1N1CCN(C3CCC3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O)(C(C)C)C(C)C
Yield: 74.5 %

Procedure:
Under nitrogen atmosphere, to the MeCN (8 ml) suspension of 9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound F4-10, 200 mg, 0.397 mmol), ethynyltriisopropylsilane (268 mg, 3.0 eq.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (39 mg, 0.2 eq.), Pd(CH3CN)2Cl2 (11 mg, 0.1 eq.) and cesium carbonate (518 mg, 4.0 eq.) were added and the mixture was stirred and heated under reflux condition until the reaction is completed. Upon the completion of the reaction, distilled water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/methanol) to obtain 8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-[(triisopropylsilanyl)-ethynyl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (179 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH2:7].C([O-])([O-])=O.[K+].[K+].O.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH:7][C:19](=[O:20])[CH2:18][O:17][CH3:16]
Reactant: Cc1csc(C)c1N
Reactant: COCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COCC(=O)Nc1c(C)csc1C

Procedure:
To 12.7 g (0.1 mol) of 2,4-dimethyl-3-aminothiophene, 13.84 g (0.1 mol) of K2CO3, 50 ml of water and 160 ml of methylene chloride are added without cooling 10.8 g (0.1 mol) of methoxyacetyl chloride.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:17])[C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.FC(F)C1N(C)N=CC=1.O>CN(C)C=O>[Br:1][C:15]1[C:11]([CH:10]([F:17])[F:9])=[N:12][N:13]([CH3:16])[CH:14]=1
Reactant: Cn1ccc(C(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: Cn1nccc1C(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(Br)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
At from 3 to 5° C., a solution of N-bromosuccinimide (NBS, 54 g, 0.3 mol) in dimethyl-formamide (DMF, 100 ml) was added dropwise to a solution of 3-difluoromethyl-N-methylpyrazole (49.3 g, 0.3 mol; 81.4% pure according to GC analysis) comprising, as minor component, 5.2% of 5-difluoromethyl-N-methylpyrazole, based on the total amount of the isomer mixture, in DMF (100 ml). The reaction mixture was then warmed to room temperature and stirred for a further 12 h. With stirring, the reaction mixture was then poured into water (1000 ml) and extracted twice with methyl tert-butyl ether (MTBE, 300 ml). The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and then freed from the solvent under reduced pressure. 4-Bromo-3-difluoromethyl-N-methylpyrazole was obtained as an oil (76.6 g; purity: 74.2% according to GC analysis) comprising 4.5% of unreacted 5-difluoromethyl-N-methylpyrazole. This corresponds to a yield of 89%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2OCc2ccccc2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.05 g, 0.006 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (3.30 g, 0.026 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-3-(2-benzyloxy-phenoxy)-4-bromo-but-2-enoic acid ethyl ester (2.00 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(2-benzyloxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (360 mg, 14%) as a yellow oil.
Reaction SMILES: [O:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15]>O1CCCC1>[O:1]1[C:5]([NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[CH:4][CH:3]=[N:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccno1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccno1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 53.9 %

Procedure:
To a solution of isoxazole-5-amine (740 mg, 8.80 mmol) and pyridine (2.14 ml, 26.4 mmol) in tetrahydrofuran (10 ml) was added 2,2,2-trichloroethyl chloroformate (1.82 ml, 13.2 mmol) with ice-cooling and the mixture was stirred for 40 minutes with ice-cooling. To the mixture was further added 2,2,2-trichloroethyl chloroformate (1.82 ml, 13.2 mmol) with ice-cooling and the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (1.23 g, 53.9%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[C:6]([CH3:10])(C)[CH:5]=[C:4]([C:11]([CH3:21])=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=2)[CH:3]=1.[CH2:22](C1OC1)Cl.C(O)(C)C.[OH-].[Na+]>O>[CH3:10][C:6]1[CH:5]=[C:4]([C:11]([CH3:21])=[CH:12][C:13]2[CH:14]=[C:15]([CH3:20])[C:16]([OH:19])=[C:17]([CH3:22])[CH:18]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:8]
Reactant: ClCC1CO1
Reactant: CC(=Cc1ccc(O)c(C)c1)C1=CC(C)(C)C(O)C(C)=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=Cc1cc(C)c(O)c(C)c1)c1cc(C)c(O)c(C)c1
Temperature: 55 °C

Procedure:
3,3',5,5-Tetramethyl-4,4'-dihydroxy-alphamethylstilbene (211.78 grams, 1.50 hydroxyl equivalent) from A. above, epichlorohydrin (693.98 grams, 7.50 moles), deionized water (60.35 grams, 8.0 percent by weight of the epichlorohydrin used) and isopropanol (373.68 grams, 35 percent by weight of the epichlorohydrin used) are added to a two liter glass resin kettle reactor equipped with a chilled water condenser, mechanical stirrer, nitrogen purge (1 liter per minute), thermometer and thermostatically controlled infrared heating lamps and heated to 55° C. with stirring under a nitrogen atmosphere. Once the 55° C. reaction temperature is achieved, sodium hydroxide (54.0 grams, 1.35 mole) dissolved in deionized water (216 grams) is added dropwise to the reactor over a 45 minute period, so as to maintain reaction temperature between 55 and 58° C. Ten minutes after completion of the aqueous sodium hydroxide addition, the stirring is stopped and the aqueous layer which separates from the reaction mixture is pipetted off and discarded. Stirring is resumed and after a total of twenty minutes following completion of the initial aqueous sodium hydroxide addition, a second solution of sodium hydroxide (24.0 grams, 0.60 mole) dissolved in deionized water (96 grams) is added to the reactor over a twenty minute period and so as to maintain the 55° C. reaction temperature. Fifteen minutes after completion of the aqueous sodium hydroxide addition, the recovered reaction mixture is added to a separatory funnel and washed with 500 milliliters of deionized water. The separated organic layer is washed a second time (500 milliliters deionized water), recovered and then rotary evaporated under vacuum for 45 minutes at 110° C. then 30 minutes at 140° C. and 5 mm Hg. The product is recovered (293.84 grams) as a light amber colored, transparent liquid (at 24° C.) with an epoxide equivalent weight of 227.80.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([O:22]C1C=CC=CC=1)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:22]
Reactant: C1CNCCN1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CCNCC2)c(=O)n(C)c1=O

Procedure:
Example 43 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and piperazine. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.0 Hz, 1H) 7.56 (d, J=8.0 Hz, 1H) 6.99 (t, J=8.0 Hz, 1H) 3.93 (m, 1H) 3.77 (m, 1H) 3.51 (s, 3H) 3.25 (s, 3H) 3.17 (m, 4H) 2.98 (m, 1H) 2.52 (m, 1H). [M+H] calc'd for C17H19FIN5O3, 488. found, 488.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH3:27][C:28]1([CH3:38])[CH2:33][NH:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][O:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:32]2[CH2:33][C:28]([CH3:27])([CH3:38])[O:29][CH2:30][C@H:31]2[C:34]([O:36][CH3:37])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COC(=O)[C@@H]1COC(C)(C)CN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CC(C)(C)OC[C@H]2C(=O)OC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 26.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.76 g, 1.52 mmol) was reacted with (S)-methyl 6,6-dimethylmorpholine-3-carboxylate (0.26 g, 1.52 mmol) according to the procedure as described in Example 24 to give the title compound as yellow oil (0.24 g, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]#[C:17][CH3:18])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]#[C:17][CH3:18])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCC(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of the product from Step H (ca. 51.8 mmol) in THF (100 mL) and water (20 mL) was added at 0° C. a solution of lithium hydroxide monohydrate (6.5 g, 155 mmol). The solution was stirred for 1 hour at 0° C., then warmed to room temperature. After 48 hours, the solution was concentrated in vacuo. The aqueous mixture was extracted with EtOAc, acidified at 0° C. with 10% aq. HCl soln., then extracted with three portions of dichloromethane. The combined dichloromethane extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as an orange oil (10.58 g).
Reaction SMILES: ClC(Cl)(Cl)CC(=N)O[CH:6]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([N:26]([CH3:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)[N:15]=2)=[CH:12][CH:13]=1)[CH3:7].[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40].C(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:33][N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[N:22]=[C:23]([NH2:25])[N:24]=[C:19]([C:16]2[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH:6]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])[CH3:7])=[CH:9][N:10]=3)[O:18][N:17]=2)[N:20]=1
Reactant: CC(OC(=N)CC(Cl)(Cl)Cl)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Reactant: OCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(OCC(F)(F)F)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 5 %

Procedure:
1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-3-yl]ethyl 2,2,2-trichloroethanecarboximidate (Intermediate 139, 0.497 g, 0.93 mmol) was suspended in DCE (8 mL). 2,2,2-Trifluoroethanol (0.669 mL, 9.29 mmol) and tetrafluoroboric acid diethyl ether complex (0.025 mL, 0.19 mmol) were added and the mixture was stirred at room temperature for 7 h. LCMS showed incomplete conversion, so further tetrafluoroboric acid diethyl ether complex (0.125 mL, 0.93 mmol) was added and the mixture stirred at room temperature for 21 h. DCM (100 mL) and saturated aq. sodium bicarbonate (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate and concentrated under vacuum to yield a brown solid, which was purified by FCC using a gradient of 0-5% MeOH in DCM. The crude product was then purified by preparative HPLC, Method D, to afford an off-white solid. This was further purified by FCC using a gradient of 0-3% MeOH in DCM to afford the title compound as an off-white solid (0.022 g, 5%).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.ClC1C=CC(C[CH:18]2[C:23](=[O:24])[O:22][C:21]([CH3:26])([CH3:25])[O:20][C:19]2=[O:27])=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl>>[S:1]1[C:5]([CH2:6][CH:18]2[C:23](=[O:24])[O:22][C:21]([CH3:26])([CH3:25])[O:20][C:19]2=[O:27])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Reactant: O=Cc1cc2ccccc2s1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1

Procedure:
The title compound was prepared using benzo[b]thiophene-2-carbaldehyde in place of 4-chlorobenzaldehyde using the procedure described for the preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a).
Reaction SMILES: C(OC(=O)C1C=C([C:12](=O)[N:13]([O:15]CC=C)C)C=C(N)C=1)C=C.[CH2:22]([O:25][C:26](=[O:46])[C:27]1[CH:28]=[C:29]([CH:40]=[C:41]([N+:43]([O-:45])=[O:44])[CH:42]=1)[C:30]([O:32]N1C(=O)CCC1=O)=O)[CH:23]=[CH2:24].Cl.CNO>ClCCl>[CH2:22]([O:25][C:26](=[O:46])[C:27]1[CH:42]=[C:41]([N+:43]([O-:45])=[O:44])[CH:40]=[C:29]([C:30](=[O:32])[N:13]([OH:15])[CH3:12])[CH:28]=1)[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)c1cc(N)cc(C(=O)N(C)OCC=C)c1
Reactant: C=CCOC(=O)c1cc(C(=O)ON2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Agent: CNO
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(C(=O)N(C)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Starting material (8(c)) was prepared as follows. A mixture of 7(b) (2.00 g; see Example 7), N-methylhydroxylamine hydrochloride (1.06 g) triethylamine (1.72 ml) and dichloromethane (60 ml.) was stirred at 5° for 30 minutes. It was then allowed to warm to ambient temperature and stirred for a further 16 hours. The reaction mixture was then poured directly onto a flash column eluting with ethyl acetate/hexane (50:50) to give 3-(N-methyl-hydroxycarbamoyl)-5-nitro-benzoic acid allyl ester (8(a)) as a cream solid (1.43 g).