Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4](Cl)[N:3]=1.Cl.[CH3:31][NH:32][CH3:33].C(N(C(C)C)CC)(C)C.O>N1C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4]([N:32]([CH3:33])[CH3:31])[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N(C)C)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 66.7 %

Procedure:
2-amino-6-chloro-9-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl) purine (1) [M. J. Robins and B. Uznanski, Can. J. Chem., 59, 2601-2607 (1981)](18.6 mmol, 7.96 g) was dehydrated three times azeotropically with anhydrous pyridine, and dissolved in anhydrous pyridine, then dimethylamine hydrochloride (55.8 mmol, 4.55 g) and diisopropylethylamine (74.4 mmol) were added thereto with stirring at room temperature. The mixture was stirred at room temperature for 15 hours. After confirming completion of the reaction by TLC, water was added to the reaction mixture and concentrated in vacuo. Chloroform was added to the residue, and the organic layer was washed 3 times with water, 2 times with 5% aqueous sodium hydrogen carbonate, once with water and 2 times with 10% aqueous citrate solution, then the organic layer was dried with magnesium sulfate, and dried in vacuo after filtration. The residue was treated with azeotropic distillation with toluene until no odor of pyridine was noted, the product was purified by silica-gel chromatography (dichloromethane-ethanol) to obtain the product (2) 5.42 g (12.4 mmol) (67%). 1H-NMR (500.13 MHz, CDCl3) δ: 7.56 (s, 1H, H8), 6.02 (d, 1H, H1′, J=5.0 Hz), 5.95 (dd, 1H, H2′, J=5.0 Hz), 5.79 (t, 1H, H3′, J=5.0 Hz), 4.69 (s, 2H, 2-NH2), 4.42-4.45 (m, 1H, H4′), 4.34-4.40 (m, 2H, H5′, H5″), 3.43 (br, 6H, N—CH3), 2.13, 2.10, 2.08 (s, 3H, Ac).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[NH:23][C:24]([C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)=[O:25].ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=[C:2]([N:27]2[CH2:28][CH2:29][CH2:30][C@H:26]2[C:24]([NH:23][C:19]2[S:18][CH:22]=[CH:21][N:20]=2)=[O:25])[N:7]=1
Reactant: O=C(Nc1nccs1)[C@@H]1CCCN1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1nccs1)[C@@H]1CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1

Procedure:
(S)-1-(4-Chloro-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide 109B was prepared from 1A and 109A as described for 1C. LC/MS [M+H]+: 432/434; Ret time (Method F): 2.70 min.
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][N:27]=2)[CH3:22])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O.O>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[O:24][C:23]([C@@H:21]([NH:20][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[CH:19]=[CH:18][N:17]=3)[CH3:22])=[N:27][CH:26]=2)=[CH:29][CH:30]=1
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ncc(-c2ccc(Cl)cc2)o1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1ncc(-c2ccc(Cl)cc2)o1
Yield: 37.7 %

Procedure:
(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (360 mg, 0.741 mg) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the desired product (120 mg, pale yellow foam). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=6.0 Hz, 1H), 7.64-7.49 (m, 3H), 7.49-7.35 (m, 2H), 7.29 (s, 1H), 5.33 (dd, J=9.4, 5.1 Hz, 1H), 5.04-4.81 (m, 1H), 1.80-1.69 (m, 3H), 4.71-4.53 (m, 1H), 4.45 (dd, J=9.4, 8.1 Hz, 1H), 4.28-3.97 (m, 1H), 3.51 (s, 3H), 1.14 (d, J=6.4 Hz, 3H). HRMS(B) m/z 429.1204. RT=2.22 min.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.O.CSC>[OH:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CSC
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 70 %

Procedure:
1-(3-Benzyloxybenzyl)-5-methoxy-2-phenylindole (200 mg) was dissolved in trifluoroacetic acid-water-dimethyl sulfide (95/5/10, 4.8 mL), and the solution was stirred at room temperature for 68 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8]
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)ccc1OC(=O)N1CCOCC1
Yield: 95.1 %

Procedure:
Using 5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[O:11].[ClH:12].Cl.[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][SH:29])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:2].[ClH:14].[ClH:12].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][N:20]([CH:19]([Cl:12])[C:18]2[CH:30]=[CH:31][CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22]1)[OH:11].[OH2:2].[OH2:2].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][N:20]([CH:19]([Cl:12])[C:18]2[CH:30]=[CH:31][CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22]1)[OH:11].[ClH:14].[ClH:14]
Reactant: COc1ccccc1N=C=O
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1NC(O)=[SH]CCCN1CCN(C(Cl)c2ccccc2)CC1
Product: O
Yield: 48.2 %

Procedure:
The procedure described in Example 2 was followed, using 1.3 g of 2-methoxyphenyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)piperazin--yl]propanethiol dihydrochloride, 0.9 g of triethylamine and 50 ml of methylene chloride, to give 0.9 g (20% of theory) of N-(2-methoxyphenyl)-S-{3-[4-(chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride sesquihydrate as an off-white crystalline solid, M.p. 238°-240° C.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:11][CH:10]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(F)c3F)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(F)c4F)cc3)cc21

Procedure:
Analogously to Method D, 0.600 g of tert-butyl 4-{4-[3-(2,3-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.391 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.14 (1:2 EtOAc-heptane); Rt=5.81.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:12])=[CH:5][N:6]=[CH:7]2.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(C(F)(F)F)=O>O1CCOCC1.CCCCCCC.[Pt](=O)=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]([CH3:12])[CH2:5][NH:6][CH2:7]2
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Cc1cncc2cccc(Br)c12
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2c1C(C)CNC2
Reaction time: 6 h
Yield: 125.1 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.319 g, 0.450 mmol), 5-bromo-4-methylisoquinoline (Frontier Scientific, Logan, Utah, 1.000 g, 4.50 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, San Diego, Calif., 0.990 g, 4.50 mmol), and potassium phosphate (3.82 g, 18.01 mmol) in 10 mL dioxane 5 mL water was heated to 80° C. for overnight. The reaction mixture was diluted with heptane, and the organics were separated then concentrated. The resulting residue was dissolved in 10 mL MeOH, was treated with platinum(IV) oxide (0.102 g, 0.450 mmol) and TFA (0.694 ml, 9.01 mmol) and was placed under 45 psi (4559.6 kpa) H2 overnight. LC/MS showed incomplete reaction, so an additional portion of platinum(IV) oxide (0.102 g, 0.450 mmol) and TFA (0.694 ml, 9.01 mmol) were added, and the reaction mixture was placed under 45 psi (4559.6 kpa) H2 for an additional 6 hours. The reaction mixture was then filtered through diatomaceous earth. The filtrate was poured into saturated NaHCO3 solution and extracted with EtOAc. The organics were dried over MgSO4 and concentrated yielding racemic 5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,3,4-tetrahydroisoquinoline (1.810 g, 5.63 mmol). [M+H]+=322.2
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.[Cl:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]=[C:23]=S)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.[OH2:31]>>[Cl:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([N:3]3[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]3[CH3:1])=[O:31])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: S=C=Nc1ccc(Oc2cccc(Cl)n2)cc1
Reactant: CC1CCC(C)N1
Reactant: O
Solvent: c1ccncc1
Product: CC1CCC(C)N1C(=O)Nc1ccc(Oc2cccc(Cl)n2)cc1
Reaction time: 16 h

Procedure:
2,5-Dimethylpyrrolidine (2.5 grams; 0.0284 mole) was added at ambient temperature to a solution of 4-((6-chloro-2-pyridinyl)oxy)phenyl isothiocyanate, prepared as in Example 7 (7.0 grams; 0.0284 moles) in 25 ml. of dry pyridine. The resulting reaction mixture was allowed to stand at ambient temperatures for a period of about 16 hours and then poured into 300 ml. of cold water. The resulting product precipitate was recovered by filtration, washed with water and taken up in boiling benzene. Hexane was then added to the solution and the solution cooled to precipitate the desired N-(4-((6-chloro-2-pyridinyl)oxy)phenyl)-2,5-dimethyl-1-pyrrolidine carboxamide compound as a crystalline solid having a carbon, hydrogen, nitrogen and chlorine content of 62.2, 5.7, 11.9 and 10.2 percent, respectively, as compared with contents of 62.5, 5.82, 12.5 and 10.25 percent, respectively, calculated for the named structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].ClC(OC)=O>C(Cl)Cl.CCOC(C)=O>[CH3:17][O:16][C:13]([CH3:15])([CH3:14])[C@H:9]([NH:8][C:6]([O:5][CH3:1])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: COC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)O)C(C)(C)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of Example 203B (163 mg, 0.66 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL) and the solution was stirred at room temperature for 1 h. Solvent was removed in vacuo and the residue was suspended in saturated NaHCO3, extracted with EtOAc, the organic extracts combined, washed with brine, dried (Na2SO4), filtered and solvent removed in vacuo. The residue was dissolved in dioxane (1 mL) and 1 M NaOH (1.1 mL, 2.175 mmol) was added followed by the dropwise addition of methyl chloroformate (0.102 mL, 1.3 mmol). The solution was stirred at room temperature for 16 h, diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (96 mg, 0.468 mmol, 71%).
Reaction SMILES: Br[C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCO.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>[C:7]([C:6]1[C:2]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[C:3]([C:15]([O:17][CH3:18])=[O:16])[S:4][C:5]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#[N:8]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1Br
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: [K+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of methyl 3-bromo-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate (0.040 g, 0.12 mmol), p-tolylboronic acid (0.020 g, 0.14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.004), 2M aqueous K2CO3 solution (0.120 mL, 0.24 mmol) in 1,2-dimethoxyethane/EtOH (8/2) (2 mL) was subjected to MWI at 110° C. for 10 min. The reaction mixture was concentrated; the residue was diluted with water and extracted with DCM. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography and triturated with cold MeOH to give methyl 4-cyano-3-(4-methylphenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.030 g, 83%). LCMS: (AA) ES+ 343.1. 1H NMR (400 MHz, CDCl3) δ: 7.24-7.27 (m, 4H), 3.87-3.89 (m, 4H), 3.69 (s, 3H), 3.60-3.62 (m, 4H) and 2.39 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:6][CH:5]=1.CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH:10]([O:17][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:18][CH:19]=1
Reactant: OC(COc1ccc(Cl)cc1)Cn1ccnc1
Reactant: CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCOC(COc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 56% dispersion of sodium hydride in mineral oil (480 mg.) is added under nitrogen to a solution of 2.52 g. of 1-[3'-(4"-chlorophenoxy)-2'-hydroxypropyl]imidazole in 6 ml. dry hexamethylphosphoramide. After stirring for 1 hours at room temperature, the temperature is increased to 45° C. and stirring is continued for 2 hours. The solution is then cooled in an ice bath and 2.5 g. of 1-bromodecane in 1 ml. of hexamethylphosphoramide is added. Thereafter, the solution is stirred for 2 hours at room temperature and then for 16 hours at 50° C. The reaction mixture is poured into water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue is chromatographed on silica gel. Elution with 20% acetone in dichloromethane yields 1-[3'-(4"-chlorophenoxy)-2'-(n-decyloxy)propyl]imidazole.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7])=[O:2].OS(O)(=O)=O.[CH3:18]O>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([O:8][CH3:18])=[O:7])=[O:2]
Reactant: CO
Reactant: O=Cc1cc(C(=O)O)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 84 %

Procedure:
A suspension of 3-formyl-4-hydroxybenzoic acid (3.9 g, 23.5 mmol) in of methanol (50 ml) was cooled below 0° C. To the suspension was added concentrated H2SO4 (3 ml) and the reaction was allowed to warm to ambient temperature and stirred for 60 hours. The reaction was heated to reflux for 12 hours, the solvent evaporated and residue subjected to chromatography (eluant: ethyl ether/hexane) to give methyl 3-formyl-4-hydroxybenzoate as a white solid (3.55 g, 84%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(Cl)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-chlorophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed that the resulting solid was determined to be the named product (m.p. 56° C.-57° C.).
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].I([O-])(=O)(=O)=[O:20].[Na+]>O1CCCC1.O.O.C(Cl)Cl>[CH:4]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])=[O:20]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(C=CN(C)C)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.2 g (4.8 mmol) of methyl 4-(2-dimethylaminovinyl)-3-nitrobenzoate were dissolved in 120 mL of tetrahydrofuran/water (1:1) and after the addition of 3.0 g (14.3 mmol) of sodium metaperiodate the mixture was stirred for 20 hours at ambient temperature. The suspension was then diluted with water and methylene chloride and extracted with methylene chloride. The combined organic extracts were washed with sodium hydrogen carbonate solution, dried, and evaporated down. The residue was chromatographed on silica gel and eluted with ethyl acetate/cyclohexane (1:3). Yield: 0.6 g (63% of theory); Rf value: 0.63 (silica gel, ethyl acetate/cyclohexane=1:1).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][Si](C=[N+]=[N-])(C)C.N#N.C(OCC)(=O)C>CO.C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:12])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.0 eq of 4-(bromomethyl)benzoic acid in 20 ml of methanol and 50 ml of toluene; was added dropwise 2.05 eq of trimethylsilyldiazomethane while stirring at room temperature. The reaction was titrated until a persistant pale yellow color existed from the addition of excess trimethylsilyldiazomethane. Let stir at room temperature for 1 hr to insure the complete evolution of N2. Thin layer chromatography in 1:1 hexame:ethyl acetate indicated the disappearance of starting material and the appearance of desired ester with an Rf of 0.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[C:32]([Br:33])=[CH:31][C:30]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:29][N:17]3[C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[CH:29]=[C:30]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH:31]=[C:32]([Br:33])[C:16]2=[N:15][C:14]=1[C:12]1[O:13][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:10][N:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CNC(=O)c1nc2c(Br)cc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1)Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1c(OCc2ccccc2)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(Br)cc(N3CCOCC3)cn12
Reaction time: 3 h
Yield: 18.4 %

Procedure:
To a solution of the product of example 2 (140 mg, 0.23 mmol) in acetonitrile (2 ml), carbon tetrachloride (213 mg, 1.383 mmol), triethylamine (117 mg, 1.1584 mmol) and triphenylphosphine (302 mg, 1.151 mmol) were added successively at room temperature. The mixture was stirred for 3 hours. The product was purified by column chromatography (CH2Cl2/MeOH=150/1) to give the titled compound (25 mg, 20% yield).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[C:5]([C@@:9]2([CH3:19])[NH:14][C:13](=S)[CH2:12][N:11]3[N:16]=[CH:17][CH:18]=[C:10]23)[CH:6]=[CH:7][CH:8]=1.CO>O.C([O-])([O-])=O.[Na+].[Na+]>[Br:2][C:3]1[CH:4]=[C:5]([C@@:9]2([CH3:19])[N:14]=[C:13]([NH2:1])[CH2:12][N:11]3[N:16]=[CH:17][CH:18]=[C:10]23)[CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: C[C@]1(c2cccc(Br)c2)NC(=S)Cn2nccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]1(c2cccc(Br)c2)N=C(N)Cn2nccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
32% aqueous ammonia solution (11.9 mL, 201.1 mmol) was added to a stirred mixture of (R)-4-(3-bromo-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazine-6-thione (1.8 g, 5.59 mmol) in 7 N solution of ammonia in methanol (11.97 mL, 83.79 mmol) in a sealed tube. The mixture was stirred at 60° C. for 90 minutes. After cooling to room temperature the mixture was diluted with water and Na2CO3 (aq. sat. solution) and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution of ammonia in methanol in DCM 0/100 to 2/98 to 3/97 to 10/90). The desired fractions were collected and concentrated in vacuo to yield (R)-4-(3-bromo-phenyl)-4-methyl-4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine (1.4 g, 82% yield) as a yellow solid.