Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:13]=[N:12][C:11]=3[NH:10][C:9]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:9]1[N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12][C:11]=2[N:10]=1
Reactant: O=c1[nH]c2ncn(Cc3ccccc3)c2c(=O)n1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1c2c(ncn2Cc2ccccc2)nc(Cl)n1Cc1ccccc1

Procedure:
Treat 1,7-bis(phenylmethyl)purin-2,6-dione with POCl3 in accordance with Preparative Example 4, to give the title compound, an off-white solid, EI MS: M+=350.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].[N:13]([CH2:16][Si:17]([O:21][CH3:22])([O:19][CH3:20])[CH3:18])=[C:14]=[O:15]>>[CH3:20][O:19][Si:17]([CH2:16][NH:13][C:14]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:15])([O:21][CH3:22])[CH3:18]
Reactant: CO[Si](C)(CN=C=O)OC
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C(C(=O)NC[Si](C)(OC)OC)C(=O)OC
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A stirred mixture conditioned at a temperature of 30° C. of 6.74 g of dimethyl malonate and 90.0 mg of sodium methoxide (30% strength solution in methanol) was admixed dropwise with 8.06 g of (isocyanatomethyl)-dimethoxy(methyl)silane and the clear solution was stirred for 90 min. This gave dimethyl 2-{[dimethoxy(methyl)silyl]methylcarbamoyl}malonate after recrystallization from isohexane in 56% yield with a purity of >95% (analysis by 1H NMR).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccc(Cl)c2o1
Product: Clc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 45000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (32 mg, 0.20 mmol) and 2-(but-3-ynyl)-7-chlorobenzo[d]oxazole (42 mg, 0.20 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 25 mg (90 mmol, 44%) of 7-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.
Reaction SMILES: [C:1]([CH2:11][C:12]([O:14]CC)=[O:13])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:17]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)=[N+:18]=[N-:19].[O-]CC.[Na+].O>C(O)C>[CH2:27]([NH:26][C:24]([C:23]1[CH:29]=[CH:30][C:20]([N:17]2[C:1](/[CH:2]=[CH:3]/[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:11]([C:12]([OH:14])=[O:13])[N:19]=[N:18]2)=[CH:21][CH:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)CC(=O)C=Cc1ccccc1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Ethyl cinnamoylacetate (1.17 g, 4.82 mmol, 1.2 eq.) obtained in Example 106a) and 4-azido-N-ethylbenzamide (0.750 g, 3.94 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (373 mg, 4.93 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 10.5 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (2:1, 40 ml), acidified (pH<3) with 6N hydrochloric acid, and extracted with ethyl acetate (25 ml×3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-brown powder (627 mg, 1.73 mmol, 43.9%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[NH:21][CH2:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:24]1([CH2:23][CH2:22][NH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[N:15][CH:16]=2)=[O:27])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)NCCC3CC3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCC1CC1)c1ccc(C2=CCNCC2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 5-(2-cyclopropylethylcarbamoyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.338 g, 0.910 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.7 mL). The resulting mixture was stirred at room temperature for 6 hours and then quenched with a saturated aqueous solution of Na2CO3 (5 mL). The organic phase was washed with water (10 mL), saturated NaCl (10 mL), dried over MgSO4 and then concentrated in vacuo. The crude title compound was obtained and used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:23][CH2:22][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17]C(C)(C)C)=O)=[CH:10][C:9]=3[C:5]=2[CH2:4]1.Cl.C(Cl)(=O)[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[CH3:24][N:2]([CH3:1])[CH:3]1[CH2:23][CH2:22][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[O:17])=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CN(C)C1CCc2oc3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Agent: Cl
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 35.8 %

Procedure:
Beginning with 0.100 gm (0.30 mMol) of (+)-N,N-dimethyl-8-(tert-butoxycarbonyl)amino-1,2,3,4-tetrahydro-2-dibenzofuranamine and 0.100 gm (0.56 mMol) of isonicotinoyl chloride hydrochloride, 0.036 gm (36%) of the title compound were recovered in two crops from toluene/hexane by the procedure described in Example 24.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]3[CH2:36][CH2:35][CH:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]3)[CH:26]=2)=[O:23])=[CH:17][C:16]=1[O:41][CH3:42]>O1CCCC1>[C:37]([CH:34]1[CH2:33][CH2:32][CH:31]([C:27]2[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH2:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:11][CH:1]=[O:2])=[C:16]([O:41][CH3:42])[CH:17]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:36][CH2:35]1)([CH3:38])([CH3:39])[CH3:40]
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCN
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCNC=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Formic acid (30 mg) is slowly added to acetic anhydride (75 mg), and the mixture is heated with stirring at 60° C. for 2 hours. To the mixture is added dry tetrahydrofuran (0.2 ml), and further added 4-(2-aminoethoxy)-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide (100 mg) obtained in Example 62 at −20° C. The mixture is stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (80 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:69]=[C:70]1[CH:74]=[CH:73][C:72](=[O:75])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH2:84])=[O:82]>>[O:75]=[C:72]1[CH:73]=[CH:74][C:70](=[O:69])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH:84][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([NH:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:82]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157, from 20 mg (21 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylamino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:15][C:16]1[N:17]([CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:18]2[C:23]([N:24]=1)=[CH:22][N:21]=[CH:20][N:19]=2.C(=O)([O-])O.[Na+]>C(O)C>[CH2:28]([O:27][CH2:26][CH2:25][N:17]1[C:16]([CH2:15][N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12]2)=[N:24][C:23]2[C:18]1=[N:19][CH:20]=[N:21][CH:22]=2)[CH3:29]
Reactant: CCOCCn1c(CCl)nc2cncnc21
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOCCn1c(CN2CCN(Cc3ccccc3)CC2)nc2cncnc21
Yield: 62 %

Procedure:
A mixture of 4.4 parts of 1-(phenylmethyl)piperazine, 4.7 parts of 8-(chloromethyl)-9-(2-ethoxyethyl)-9H-purine, 2.1 parts of sodium hydrogen carbonate and 40 parts of ethanol was stirred and refluxed for 5 hours. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 4.6 parts (62.0%) of 9-(2-ethoxyethyl)-8-[[4-(phenylmethyl)-1-piperazinyl]methyl]-9H-purine as a residue (compound 23).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([N+:30]([O-])=O)[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c([N+](=O)[O-])c5)cc4C3)c2C1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Reaction time: 1.5 h
Yield: 30.5 %

Procedure:
A mixture of 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3-nitropyridine-2-amine (0.5 g, 1.37 mmol) and palladium on carbon (0.5 g, 50% water) in methanol (50 mL) was hydrogenated in a Parr apparatus at 40 psi for 90 min. The mixture was filtered through celite and concentrated. Column chromatography of the residue on silica (dichloromethane/methanol 9:1) provided 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (174 mg, 30% yield over 2 steps) as a brown solid. MS (EI) for C24H28N6O: 417 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:11]\[OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a suspension of 4-chlorobenzaldehyde (25.0 g, 178 mmol) and hydroxylamine hydrochloride (13.7 g, 198 mmol) in ethanol (14.1 mL) and water (42.9 mL) was added ice (82 g). Then a solution of sodium hydroxide (18.1 g, 454 mmol) in water (21.4 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (27.0 g, 97%) which was obtained as an off white solid. MS m/e (EI): 155.1 [M]+.
Reaction SMILES: C(C(O)=O)(F)(F)F.[O:8]=[C:9]1[C:17]2([CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>C(Cl)Cl>[O:8]=[C:9]1[C:17]2([CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CCOCC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1C(=O)C2(CCOCC2)c2ccccc21
Reaction time: 3 h

Procedure:
CF3CO2H (1 mL) was added to a solution of tert-butyl (2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetate from Step B (55.0 mg, 0.173 mmol) in CH2Cl2 (3 mL). After 3 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[C:15]([OH:17])=[O:16]>Br>[OH:2][C:3]1[C:4]([C:15]([OH:17])=[O:16])=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1c(C(=O)O)cc(C(=O)O)cc1C(=O)O
Agent: Br
Product: O=C(O)c1cc(C(=O)O)c(O)c(C(=O)O)c1
Temperature: 150 °C

Procedure:
A mixture of 2-methoxy-benzene-1,3,5-tricarboxylic acid (3) (24 g, 0.1 mol) and 48% HBr (500 mL) was placed in a 1 L bound bottom flask. The reaction mixture was heated to reflux at 150° C. for 48 h. The progress of the deprotection was monitored by proton NMR. When the reaction was complete, the hydrobromic acid was removed under reduced pressure, and the residue was mixed with small amount of water. The deprotected triacid (13) was collected by filtration; yield 17 grams (75%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:10]([N+:24]([O-:26])=[O:25])[CH:9]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[CH2:27]([O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:10]([N+:24]([O-:26])=[O:25])[CH:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc(O)c2ccccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1c([N+](=O)[O-])cc(OCc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Anhydrous K2CO3 (0.50 g, 3.68 mmol) was added to a solution of ethyl 2-[4-hydroxy-2-nitronaphthalen-1-yl]acetate (0.42 g, 1.53 mmol) and benzyl bromide (0.44 mL, 3.68 mmol) in acetone (4 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was diluted with AcOEt (50 mL), and to the mixture was added N-methypiperazine (3 mL) to remove any excess benzyl bromide. The mixture was washed with water (10 mL), 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL), and then dried (Na2SO4) and evaporated to yield ethyl 2-[4-benzyloxy-2-nitronaphthalen-1-yl]acetate (0.35 g, 63%) as a yellow solid. Mp 128-130° C.; 1H NMR (CDCl3, 500 MHz) δ 8.44 (dd, 0.5, 8.0, 1H), 8.10 (d, 8.5, 1H), 7.71 (t, 7.0, 1H), 7.66 (t, 7.0, 1H), 7.54 (d, 7.0, 2H), 7.46 (t, 7.5, 2H), 7.43 (s, 1H), 7.40 (t, 7.0, 1H), 5.32 (s, 2H), 4.33 (s, 2H), 4.21 (q, 7.0, 2H), 1.27 (t, 7.0, 3H); EIMS m/z 365 (M+); IR (neat) νmax 2980, 1725, 1592, 1524, 1512, 1469, 1451, 1426, 1371, 1331, 1252, 1202, 1159, 1111, 1022, 842, 770, 756, 724, 690 cm−1.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[O-2].[Zn+2:7]>>[C:1]([O-:5])(=[O:4])[CH2:2][CH3:3].[Zn+2:7].[C:1]([O-:5])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Product: CCC(=O)[O-]
Yield: 90 %

Procedure:
In one embodiment of the present invention, anhydrous propionic acid was mixed with dry zinc oxide to yield greater than 90 percent zinc propionate. The resulting zinc propionate was a white powder, and was in a form readily utilizable for dietary supplementation. Unlike the conventional aqueous method of preparation, the product is not precipitated and then separated from solution. Moreover, no drying of the product by vacuum desiccation, spray drying or freeze drying is required, thereby saving energy costs. In comparison, using the conventional method where the zinc oxide was dissolved in an aqueous solution of propionic acid, and the solution was heated to boiling and evaporated to yield zinc propionate crystals, the yield of zinc propionate was 75.2 percent, after two crystallizations and drying under reduced pressure for 16 hours.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1
Product: Clc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-chloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.Cl.C(O[C:14](=N)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)C>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: CCOC(=N)COc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cc1N
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-phenylene-diamine (19.2 g, 0.103 mol) and 2-(4-trifluoromethyl-phenoxy)-acetimidic acid ethyl ester hydrochloride (35.0 g, 0.123 mol) in EtOH (377 mL) was stirred at room temperature for 12 hours. The reaction was concentrated to give a brown solid, which was partitioned between EtOAc and water. The organic fraction(s) were washed with brine, dried over Na2SO4, and the filtrate was concentrated to afford the title compound as a brown solid (100%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.74 (s, 1H), 7.62 (d, 2H, J=8.0 Hz), 7.50 (d, 1H, J=8.8 Hz), 7.39 (dd, 1H, J=8.4 Hz, J=1.6 Hz), 7.23 (d, 2H, J=8.4 Hz), 5.41 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C15H11BrF3N2O: 372.2 (M+H), Found 372.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10](Cl)(=[O:14])[C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:10](=[O:14])[C:11](=[O:12])[S:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(S)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: COc1ccc2c(c1)SC(=O)C2=O
Temperature: 25 °C
Yield: 47 %

Procedure:
To a solution of 3-methoxythiophenol (26.7 mmol) in ether (20 mL) was added oxalyl chloride (43 mmol) dropwise. The mixture was heated at reflux for 1.5 h, cooled to rt, and concentrated in vacuo. The resulting yellow oil was dissolved in dichloromethane (50 mL), cooled to 0° C., and was treated with aluminum chloride (32.0 mmol) in portions. The mixture was heated at reflux for 30 min, cooled to rt, and poured onto ice water with stirring. The organic layer was separated and successively washed with saturated, aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (4/1 ethyl acetate/hexane) which provided 6-methoxy-1-benzothiophene-2,3-dione (47%) as an orange solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[C:11]([O:15][C:16](=[O:27])[NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12]>C(#N)C>[C:11]([O:15][C:16](=[O:27])[NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:3][CH:2]=[CH2:1])=[CH:22][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reaction time: 12 h

Procedure:
Allyl bromide (2.10 ml, 24.8 mmol) was added in one portion to a suspension of potassium carbonate (4.40 g, 31.8 mmol) and tert-butyl[2-(4-hydroxyphenyl)ethyl]carbamate (Prepared according to Journal of Organic Chemistry 1999, 64, 1074, 5.00 g, 21.1 mmol) in acetonitrile (50 ml) at room temperature. The reaction was stirred for 12 hours and the solvent removed in vacuo. Diethyl ether (50 ml) and water (20 ml) were added and the organics separated, washed with water (20 ml), dried (magnesium sulphate) and the solvent removed in vacuo to yield a clear oil. The oil was purified by column chromatography on silica gel eluting with ethyl acetate:pentane (25/75 by volume) to furnish the title compound as a white solid, 3.80 g.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][C:10]1([CH2:16][OH:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C>[OH:17][CH2:16][C:10]1([CH2:9][NH:8][C:2]2[CH2:6][S:5][C:4](=[O:7])[N:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=C1NC(=S)CS1
Reactant: NCC1(CO)CCOCC1
Solvent: CCO
Product: O=C1N=C(NCC2(CO)CCOCC2)CS1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (898 mg) in ethanol (15 mL) was added a solution (5 mL) of [4-(aminomethyl)tetrahydro-2H-pyran-4-yl]methanol (1.00 g) in ethanol, and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, the precipitate was collected by filtration, and the obtained powder was washed with ethyl acetate to give the title compound (1.44 g).