Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH:43]1[C:48](=[O:52])[NH:49][O:50][CH3:51])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:3]=3[C:2]([F:1])([F:33])[F:34])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44][CH:43]1[C:48](=[O:52])[NH:49][O:50][CH3:51])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CONC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CONC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-methoxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Methoxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1-c1ccccc1

Procedure:
In 10 ml of acetonitrile, 1.0 g of o-phenylphenol and 1.29 ml of ethyl bromoacetate were added in the presence of 1.76 ml of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and the resultant mixture was refluxed for 8 hr. The reaction mixture was treated similarly to that in Example 28 (Process 2) to give 1.46 g of ethyl o-phenylphenoxyacetate. The ester was dissolved in 30 ml of ethanol, mixed with 10.8 ml of 1N-NaOH aqueous solution and stirred for 12 hr. The reaction mixture was evaporated under reduced pressure, acidified by the addition of 1N-HCl and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and o-phenylphenoxyacetic acid was crystallized as DCHA salt from ether with the yield of 1.59 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[CH:3]=1)[O:10][C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1
Reactant: Oc1cncnc1
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Br)cc(Oc2cncnc2)c1
Yield: 53.6 %

Procedure:
1-Bromo-3-chloro-5-fluorobenzene (1.0 g, 4.8 mmol, 1.0 eq), 5-hydroxypyrimidine (454 mg, 5.02 mmol, 1.05 eq), K2CO3 (792 mg, 5.73 mmol, 1.20 eq) and DMF (15 mL) were added to a microwave vial and microwaved at 200° C. for 30 minutes. The reaction was filtered and concentrated on silica gel (5 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 735 mg (43%) of the title compound as a golden oil: 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.73 (s, 2H), 7.58 (t, J=1.7 Hz, 1H), 7.43 (t, J=1.9 Hz, 1H), 7.35 (t, J=2.0 Hz, 1H); ES-MS [M+1]+: 285.0.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Cl:12]Cl>C(O)(=O)C>[Cl:12][C:10]1[CH:11]=[C:3]([CH:4]=[C:5]([O:6][CH3:7])[C:8]=1[OH:9])[CH:2]=[O:1]
Reactant: ClCl
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(Cl)c1O
Reaction time: 0.5 h

Procedure:
Compound 12 was prepared according to the procedure of Hann et al. (J. Am. Chem. Soc. 1927, 49, 535-7). To a solution of 2.50 g (16.4 mmol) of vanillin in 15 mL of glacial acetic acid was added chlorine gas through a glass tubing over 30 minutes (with a slow gas flow) at 25° C. White solid product was collected by filtration, washed with 50 mL of hexane, and dried in vacuo to give 2.033 g of 12. The acetic acid filtrate was again treated with chlorine gas as above for 30 minutes to give another 0.659 g of 12. A total of 2.691 g (88% yield) of 12 was obtained. The white solids were used in next step without purification. 1H NMR (CDCl3) δ 10.04 (s, 1H, OH), 9.76 (s, 1H, CHO), 7.56 (d, J=1.6 Hz, 1H, Ar), 7.37 (d, J=1.6Hz, 1H, Ar), 3.91 (s, 3H, OMe); 13C NMR (CDCl3) δ 190.5 (C═O), 149.0 (s, 2C), 128.2 (s), 125.6 (d), 120.1 (s), 109.2 (d), 56.3 (q).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=[O:5])C.Cl.[C:19](N)(=[NH:21])[CH3:20]>C(O)C>[CH3:20][C:19]1[NH:21][C:4](=[O:5])[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][S:8][C:7]=2[N:17]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: CC(=N)N
Agent: Cl
Solvent: CCO
Product: Cc1nc2scc(-c3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43 g, 1.54 mol), acetamidine hydrochloride (725.13 g, 7.676 mol) and ethanol (1500 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 2-Methyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]#N)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:23].[Na+].C[OH:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([OH:26])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C#N)CC1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C(=O)O)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-(4-chloro-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.6 g, 1.86 mmol) in methanol (4.0 mL) was added 1.0 N NaOH (4.0 mL, 4.0 mmol) and the resulting mixture was heated to reflux at 80° C. for 36 h. Additional 1.0 N NaOH (2.0 ml, 2.0 mmol) was added to the reaction mixture and refluxed further for 18 hrs. The reaction mixture was concentrated and acidified to pH 4.0-5.0 using 1.0 N HCl and extracted with chloroform (5×). The combined organics were dried over sodium sulfate, concentrated and dried in vacuo overnight. The product contained approximately 20% amide and was separated after esterification in the next step. ESI-MS m/z: 341 (M+1), UV retention time: 2.33 min.
Reaction SMILES: [OH:1][C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[C:6]1([OH:15])[C:5]1[CH:16]=[C:17]([CH2:20][CH2:21][CH3:22])[CH:18]=[CH:19][C:4]=1[O:3]2.[C:23]([OH:26])(=O)[CH3:24].N1C=CC=CC=1.C1C[O:36][CH2:35][CH2:34]1>>[C:35]([O:3][C:4]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][C:5]=1[C:6]1([O:15][C:23](=[O:26])[CH3:24])[C:7](=[O:14])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:1])(=[O:36])[CH3:34]
Reactant: CCCc1ccc2c(c1)C1(O)C(=O)c3ccccc3C1(O)O2
Reactant: CC(=O)O
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: CCCc1ccc(OC(C)=O)c(C2(OC(C)=O)C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
4b,9b-Dihydroxy-8-propyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.80 g, 2.70 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.55 ml, 5.40 mmol), pyridine (0.21 ml, 2.7 mmol), and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.85 g, 56%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:8]=[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: Nc1ccc(Cc2ccccc2)cc1Br
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: Nc1ccc(Cc2ccccc2)cc1-c1ccc(Cl)c(Cl)c1

Procedure:
2-bromo-4-benzylaniline and 3,4-dichlorobenzene boronic acid can be combined to form 2-(3,4-dichlorophenyl)-4-benzylaniline,
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15]1[CH2:20][CH:19]3[CH2:21][CH:16]1[CH2:17][NH:18]3)(=[O:14])=[O:13])=[CH:7]2.CCCCC[CH2:27][CH3:28].ClC(OC)=[O:31]>O1CCOCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15]1[CH2:20][CH:19]3[CH2:21][CH:16]1[CH2:17][N:18]3[C:27]([CH3:28])=[O:31])(=[O:13])=[O:14])=[CH:7]2
Reactant: CCCCCCC
Reactant: COC(=O)Cl
Reactant: O=S(=O)(c1ccc2c(Cl)cccc2c1)N1CC2CC1CN2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)N1CC2CC1CN2S(=O)(=O)c1ccc2c(Cl)cccc2c1
Reaction time: 1 h

Procedure:
The title compound was prepared from 2-(5-Chloro-2-naphthylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane, by dissolving the heptane (0.29 g, 0.8 mmol) in 20 ml dioxane and 1 ml of 1N NaOH solution. The solution was cooled with an ice bath. Methyl chloroformate (0.062 ml, 0.8 mmol) was added dropwise. Additional 1N NaOH solution was added to keep the pH above 9. After 1 hour at room temperature, the solvent was evaporated. The residue was partitioned between chloroform and saturated sodium bicarbonate solution. The aqueous layer was extracted three times with chloroform. After drying over magnesium sulfate, the solvent was evaporated to give a yellow foam. This was purified by chromatotron using 3/2 hexane/ethyl acetate to give 0.27 g (87% yield) of a white solid: mp 151°-152° C.; 1H NMR (CDCl3): 8.41-8-37 (m, 2 H, H1 and H3), 7.95-7-89 (m, 2 H, H4 and H6), 7.71 (d, J=7.4, 1 H, H8), 7.53 (t, J=7.8, 1 H, H7), 4.58 (s, 1 H, alkyl H), 4.49 (s, 1 H, alkyl H), 3.68 (s, 1 H, alkyl H), 3.55-3.46 (m, 4 H, alkyl H's), 1.70 (d, J=10.1, 1 H, alkyl H), 1.33-1.28 (m, 1 H, alkyl H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:13]=[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)(=O)C.ClCCCl>[O:13]=[C:14]1[N:18]([CH:19]2[CH2:20][CH2:21][N:22]([CH:2]3[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]3)[CH2:23][CH2:24]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)C1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.9 %

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (1.86 g), 4-(2-oxo-1-benzimidazolinyl)piperidine (1.98 g), 1,2-dichloroethane (40 mL), glacial acetic acid (0.52 mL) and sodium triacetoxyborohydride (3.47 g) was stirred at room temperature for 72 h. The reaction mixture was poured into dichloromethane (50 mL) and saturated Na2CO3 (50 mL) and the layers separated. The aqueous layer was extracted with 2×50 mL of dichloromethane and the combined organic layers dried over MgSO4 and concentrated to dryness under reduced pressure. The crude product was purified by flash column chromatography on silica, eluting with a gradient of ethyl acetate; 0-8% methanol to yield the cis and trans isomers of ethyl 1-[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]cyclohexane4-carboxylate as a colorless solid (2.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[CH3:14][C:15]1([CH:23]=O)[C@@H:20]([CH3:21])[CH2:19][CH2:18][C@H:17](C)[CH2:16]1.O(C(C)C)[CH:26](C)C>>[CH3:23][C:15]1([CH3:14])[CH2:16][CH2:17][CH2:18][C@@H:19]([CH3:26])[C@@H:20]1/[CH:21]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: CC(C)OC(C)C
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: C[C@H]1CC[C@H](C)C(C)(C=O)C1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)/C=C/[C@H]1[C@H](C)CCCC1(C)C
Reaction time: 2.5 h
Yield: 41 %

Procedure:
Trimethyl phosphonoacetate (200 g, 1.1 mol) was added dropwise to a suspension of NaH (44 g, 55% in oil, 1.1 mol) in iPr2O (1600 ml). After 2.5 hours, a solution of trans 2,3,6-trimethyl-2-cyclohexanecarbaldehyde [see C. Chapuis, R. Brauchli, Helv. Chim. Acta 1993, 76, 2070.] (91 g, 0.59 mol) in iPr2O (400 ml) was added dropwise. After 18 hours at 20° C., the reaction mixture was poured onto ice and extracted to neutrality with brine, dried (Na2SO4), concentrated and distilled through a 15 cm Vigreux column to afford the pure desired product in 41% yield.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][CH2:25][O:24]4)[C:5](=[O:17])[N:6]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][O:13]1.O.[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)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>[CH3:30][N:31]([CH3:41])[C:32]1[N:33]=[CH:34][C:35]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:21][O:20][C:19]4[CH:22]=[C:23]5[C:27](=[CH:28][C:18]2=4)[CH2:26][CH2:25][O:24]5)[C:5](=[O:17])[N:6]3[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)=[CH:36][CH:37]=1
Reactant: O=C1N(C[C@H]2CCCO2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: CN(C)c1ccc(B(O)O)cn1
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: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)CCO5)C(=O)N3C[C@H]2CCCO2)cn1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
A stirred solution of 4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.125 g, 0.3 mmol), 2-(dimethylamino)pyridine 5-boronic acid hydrate (0.08 g, 0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol), 2 M sodium carbonate (1 mL) in N,N-dimethylformamide (4 mL) was heated with stirring at 150° C. for 15 min in a microwave reactor. The solution was poured into distilled water (15 mL) and washed with ethyl acetate (75 mL). The ethyl acetate layer was washed with brine (3×25 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (gradient: 30% to 60%) to afford 4′-[6-(dimethylamino)pyridin-3-yl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.11 g, 73%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.53 (d, J=2.4 Hz, 1H), 7.33 (dd, J=7.8 Hz, 1H), 7.18 (dd, J=7.4, 4.7 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 6.71 (ddd, J=8.8, 2.4, 0.9 Hz, 1H), 6.51 (d, J=5.6 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 6.12 (d, J=0.9 Hz, 1H), 4.59-4.41 (m, 3H), 4.33 (dd, J=9.4, 3.1 Hz, 1H), 4.23-4.08 (m, 1H), 3.89-3.55 (m, 4H), 3.09-2.86 (m, 2H), 2.95 (s, 6H), 2.05-1.69 (m, 3H), 1.67-1.51 (m, 1H); MS (ES+) m/z 484.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:9])[N:3]=1
Reactant: Fc1ccc(F)c(F)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)nc1F
Temperature: 60 °C
Yield: 56.7 %

Procedure:
To a 3-neck, round-bottomed flask was added 2,3,6-trifluoropyridine (25 g, 0.19 mol) followed by the addition of red fuming nitric acid (210 mL, 4.7 mol). Sulfuric acid (150 mL, 2.8 mol) was added to this mixture slowly via an addition funnel, maintaining internal temperature below 40° C. The resulting solution was heated to 60° C. for 30 minutes and allowed to cool to room temperature after heating. This solution was then further cooled in an ice-water bath and inversely quenched into a 2-L Erlenmeyer flask containing a mixture of ice and water (700 mL, 1:1 ratio). The quenched solution was then transferred to a 2-L separatory funnel and partitioned with hexanes (600 mL). The aqueous layer was subsequently washed with hexanes (600 mL) and methylene chloride (600 mL). The combined organic layers were then dried over Na2SO4, filtered, and concentrated to provide the title compound as a light yellow liquid (19.2 g, 57% yield).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]([NH2:13])[N:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]([NH2:13])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)cc(-c2nccs2)n1
Product: Nc1nc(Cl)cc(-c2nccs2)n1
Temperature: 120 °C
Yield: 60 %

Procedure:
A suspension of the 4-hydroxy-6-(2-thiazolyl)pyrimidine-2-amine (2.64 g, 13.6 mmol) in POCl3 (30 mL) was heated at 120° C. for 3 h, cooled and concentrated in vacuo. The resulting brown solid was added to ice/water (200 g), basified with NH4OH (8 mL), filtered and purified by chromatography [SiO2; EtOAc:isohexane (2:3-1:0)] to give the title compound (1.73 g, 60%) as a pale yellow solid; NMR δH (400 MHz, DMSO) 7.22 (1H, s), 7.40 (2H, br s), 8.01 (1H, d, J 3.2 Hz) and 8.07 (1H, d, J 3.2 Hz); M/Z 213, 215 (M+H)+
Reaction SMILES: [CH3:1][CH2:2][CH3:3].[Br:4][Br:5]>>[Br:4][Br:5].[Br:4][CH:2]([CH3:3])[CH3:1].[Br:4][CH2:1][CH2:2][CH3:3]
Reactant: CCC
Agent: BrBr
Product: CC(C)Br
Product: CCCBr
Temperature: 270 °C
Yield: 88.9 %
Yield: 11.1 %

Procedure:
A mixture of propane (6.0 ml/minute) and bromine (Br2 0.30 ml/hour) was passed into a reactor (glass tube ID 0.38″, heating zone length 4″), which was heated to 270° C. The effluent was analyzed by GC/MS. 100% bromine conversion with 88.9% 2-bromopropane selectivity and 11.1% 1-bromopropane selectivity were obtained.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH:10]1([K])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(Cl)(=O)C(Cl)=O.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:3](=[O:5])[CH:2]2[O:1][CH:6]2[C:7]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)C1OC1C(=O)O
Reactant: NC1CCCCC1
Reactant: [K]C1CCCC1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(NC1CCCCC1)C1OC1C(=O)OC1CCCC1
Yield: 42.7 %

Procedure:
Following the procedure of Example 1, monocyclopentyl potassium epoxysuccinate (5.0 g) was successively treated with oxalyl chloride (2.55 g) and cyclohexylamine (3.96 g) to give 2.5 g of cyclopentyl N-cyclohexyl-2,3-epoxysuccinamate (Compound No. 25) as colorless needles melting at 93°-97° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.[K+].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].O>CS(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=2)(=[O:30])=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine in 40 ml of DMSO 3.7 g of 4-tert.-butylbenzene sulfonamide potassium salt was added. The resulting solution was stirred for 20 h at room temperature. Eventually, the mixture was poured onto 400 ml of water and washed twice with 200 ml of diethyl ether. The organic layers was extracted with 200 ml of water. The combinded aqueous layers was acidified with conc. hydrochloric acid. The mixture was cooled to 0° C. and 100 ml of brine was added. The precipitate that formed was collected and dried to yield 2.7 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=5.80 min, [M+1]+=448.17, [M−1]−=446.21.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].Br[CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: C#Cc1cccc(N)c1
Reactant: CCOP(=O)(CCBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#Cc1cccc(NCCP(=O)(OCC)OCC)c1
Yield: 7.2 %

Procedure:
3-Ethynyl aniline (2.36 g, 22.1 mmol), diethyl 2-bromoethylphosphonate (5.41 g, 22.1 mmol) and potassium carbonate (3.1 gm, 22.1 mmol) were heated at 90° C. in anhydrous acetonitrile (40 mL) for 26 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate:hexanes followed by 97:3 methylene chloride:methanol to provide diethyl 2-(3-ethynylphenylamino)ethylphosphonate (450 mg) as a yellow oil. 1H NMR (CDCl3) δ 7.15 (t, 1H), 6.83 (d, 1H), 6.70 (br s, 1H), 6.60 (m, 1H), 4.10 (m, 4H), 3.41 (m, 2H), 3.00 (s, 1H), 2.10 (m, 2H), 1.35 ppm (m, 6H). MW=281 confirmed by LC-MS, tr=11.65 min (Method Y) MH+=282.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24](OC)=[CH:23][CH:22]=1.[C:29]([O-:33])(=O)[CH2:30][OH:31].[Na+].[Na].C(O)[CH2:37][OH:38]>>[OH:31][CH2:30][CH2:29][O:33][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH3:37]
Reactant: OCCO
Reactant: COc1ccc(Cc2c(Cl)ncnc2NS(=O)(=O)c2ccc(OC)cc2)cc1
Reactant: O=C([O-])CO
Agent: [Na+]
Agent: [Na]
Product: COc1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Cc2ccccc2OC)cc1
Temperature: 125 °C

Procedure:
300 mg of N-[6-chloro-5-(p-methoxybenzyl)-4-pyrimidinyl]-p-methoxybenzenesulfonamide were added to a sodium glycolate solution from 1 ml of dry ethylene glycol and 46 mg of sodium. The reaction mixture was heated at 125° C. for 4 hours under an argon atmosphere. Thereafter, the ethylene glycol was distilled under reduced pressure. The residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase was washed neutral, dried and evaporated. The residue was chromatographed on silica gel with methylene chloride/ethyl acetate (1:1 v/v). There were obtained 250 mg of N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl]-p-methoxybenzenesulfonamide, melting point 161°-162° C.