Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:17]([O-])(O)=O.[Na+]>CO>[OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C([O-])O
Reactant: Cc1cccc(C(=O)O)c1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(C)c1O
Yield: 84 %

Procedure:
2-Hydroxy-3-methylbenzoic acid (24.9 g, 0.164 mol) was dissolved in methanol (200 mL), then sulfuric acid (1.75 mL, 32.8 mmol) was added thereto, and then the reaction mixture was refluxed for 7 days. After the reaction mixture was poured into saturated aqueous NaHCO3 solution (300 mL), methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (500 mL), then the organic layer was washed with saturated aqueous NaHCO3 solution (200 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the titled reference compound (23.0 g) as a pale brown oil. (Yield 84%)
Reaction SMILES: [Cl:1][C:2]1([Cl:18])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C:19](Cl)(=[O:21])[CH3:20]>CCO>[Cl:1][C:2]1([Cl:18])[C@@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:19](=[O:21])[CH3:20])=[CH:15][CH:16]=1
Reactant: Oc1ccc([C@H]2[C@H](c3ccccc3)C2(Cl)Cl)cc1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CC(=O)Oc1ccc([C@H]2[C@H](c3ccccc3)C2(Cl)Cl)cc1

Procedure:
The reaction of 1,1-dichloro-trans-2-(p-hydroxyphenyl)-3-phenylcyclopropane (Compound 17) (0.005 mol) and 0.4 mL of acetyl chloride yielded off-white needles (0.37 g, 22%) from EtOH, mp 124.5°-125.5° C. 1H NMR (CDCl3) δ 2.32 (s, 3H, OCOCH3), 3.20 (s, 2H, ArCH), 6.80-7.58 (m, 9H, ArH).
Reaction SMILES: [CH:1]1[C:11]2[CH:10](O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:19][CH:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:7][S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2CSc2ccccc21
Solvent: c1ccccc1
Product: ClC1c2ccccc2CSc2ccccc21

Procedure:
19.5 G. of 6,11-dihydro-dibenzo[b,e]thiepin-11-ol, 25 ml. of thionyl chloride and 180 ml. of absolute benzene are heated under reflux conditions for 2 hours. The mixture is evaporated, treated several times with absolute benzene and then evaporated. The crude 11-chloro-6,11-dihydro-dibenzo[b,e]thiepin obtained as the residue is used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC(O)=O.CC(O)=O.[Pd]>[N:22]1([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:15][CH:14]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([NH:28][C:29]3[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:3]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: Nc1ccccc1N
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1ccccc1Nc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A degassed mixture of 2-chloro-4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)thieno[3,2-d]pyrimidine (400 mg, 0.98 mmol), 1,2-diaminobenzene (240 mg, 2.22 mmol), Pd(Oac)2 (64 mg, 0.29 mmol), rac-BINAP (88 mg, 0.14 mmol) and Cs2CO3 (480 mg, 1.47 mmol) in 1,4-dioxane (4 mL)) was subjected to microwave irradiation at 150° C. for 30 minutes. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 96:4) to afford N-[4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl]benzene-1,2-diamine as a pale yellow oil (310 mg, 66%). LCMS (Method C): RT=2.06 min, [M+H]− 482.4
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]([CH3:23])[CH:16]([OH:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]([CH3:23])[CH:16]([O:22][C:28](=[O:30])[CH3:29])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(OC(C)=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 3 h

Procedure:
5 g of methyl 4-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-hydroxypentanoate were dissolved in 35 ml of methylene chloride at 0° C. 0.9 ml of acetyl chloride and then 0.94 ml of triethylamine were added dropwise under nitrogen. After 18.5 hours of standing at room temperature and three hours of reflux, an additional 0.9 ml of acetyl chloride and 0.94 ml of triethylamine were added. The mixture was washed with water dilute acid and brine. The product was purified using silica gel chromatography and identified as the above methyl-3-acetoxy ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCO>[CH2:25]([O:24][C:22]([C:21]1[N:18]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[S:17][CH:20]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (131 mg, 0.50 mmol) and ethyl bromopyruvate (74 μl, 0.50 mmol) in EtOH (3 ml) was stirred at 60° C. for 18 hours. The solid was filtered off and washed with cold EtOH, then dried in vacuo to give the title compound as light brown solid (130 mg, 72%). MS ISP (m/e): 359.1 (100) [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([O:14][C@@H:15]([C@H:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH3:16])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH:9]1([N:6]2[C:5]3[C:12]([O:14][C@@H:15]([C@H:17]4[CH2:21][NH:20][C:19](=[O:22])[CH2:18]4)[CH3:16])=[CH:13][C:2]([C:28]4[CH:33]=[N:32][CH:31]=[CH:30][N:29]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:11][CH2:10]1
Reactant: C[C@@H](Oc1cc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(-c2cnccn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 130 °C
Yield: 23 %

Procedure:
Into a microwave-tube, a mixture of (R)-4-((R)-1-((5-bromo-1-cyclopropyl-1 h-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (100.0 mg, 0.27 mmol), 2-(tributylstannyl)pyrazine (152.0 mg, 0.91 mmol), Bis(triphenylphosphine)palladium(II) dichloride (28.9 mg, 0.04 mmol) and dioxane (8 mL). The reaction mixture was placed in the microwave reactor and heated at 130° C. for 30 min. Quenched with saturated KF, extracted with EtOAc (3×30 ml). The combined organic layers were washed with water (2×5 mL), concentrated, and purified by flash chromatography (100% EtOAc to 20% MeOH/EtOAc) to give 23.0 mg (23.0%) of (R)-4-((R)-1-((1-cyclopropyl-5-(pyrazin-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 9.34 (d, J=1.8 Hz, 1H), 8.69 (dd, J=1.8, 1.2 Hz, 1H), 8.56 (d, J=2.1 Hz 1H), 8.174 (s, 1H), 8.016 (d, J=0.9 Hz 1H), 7.62 (d, J=6 Hz 2H), 4.91-4.85 (m, 1H), 3.76-3.695 (m, 1H), 3.41 (t, J=9.2 Hz, 1H), 3.20 (dd, J=6.6, 6.9 Hz, 1H), 2.87-2.80 (m, 1H), 2.41-2.24 (m, 2H), 1.34 (d, J=6 Hz, 3H), 1.23-1.0 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd C20H21N5O2:363.17; found 364.09.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[S:14][C:13]([NH:15][C:16](=[O:18])[CH3:17])=[N:12][CH:11]=1.O>CC(C)=O>[Br:9][C:10]1[S:14][C:13]([N:15]([CH3:1])[C:16](=[O:18])[CH3:17])=[N:12][CH:11]=1
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: CC(=O)N(C)c1ncc(Br)s1
Yield: 36.8 %

Procedure:
1.9 g (14 mmol) of potassium carbonate and 3.94 ml (63.3 mmol) of methyl iodide are added to a solution of 2.8 g (12.7 mmol) of N-(5-bromothiazol-2-yl)acetamide in 50 ml of acetone. The reaction medium is refluxed for 3 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1.1 g (36%) of N-(5-Bromothiazol-2-yl)-N-methylacetamide are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[N:16]=[C:17](Cl)[S:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2csc(Cl)n2)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2csc(-c3ccccc3)n2)c1

Procedure:
{3-[(2-Chloro-thiazole-4-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (114 mg, 0.35 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated for 140 min. The crude residue was purified by column chromatography using 33% EtOAc in heptane to give the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1Br)[C:9]([O:11]C)=[O:10])(=O)C.[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.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>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:9]([OH:11])=[O:10])[CH:13]=[CH:14][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:26]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(COC(C)=O)c1
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: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1CO
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of methyl 3-[(acetyloxy)methyl]-4-bromobenzoate (4.7 g, 16.4 mmol), o-tolylboronic acid (2.45 g, 18 mmol), potassium carbonate (11.3 g, 82 mmol) and Pd(PPh3)4 (1.89 g, 1.64 mmol) in toluene (23.5 mL) and water (23.5 mL) was refluxed for 2 hours. After cooling to RT, the reaction mixture was filtered through a pad of Celite which was further washed with toluene (50 mL). The filtrate was concentrated in vacuo. The residue taken up in EtOAc (250 mL) and washed with a saturated aqueous solution of NaHCO3, water and brine, dried over magnesium sulphate and concentrated under vacuum. The residue was taken up with EtOH (180 mL) and treated with a 5N aqueous solution of NaOH (12 mL, 60 mmol) at 60° C. for 1.5 hours. The reaction mixture was concentrated under vacuum. The residue was taken up in water (500 mL) and the aqueous layer was washed twice with EtOAc (2×200 mL). The aqueous layer was acidified with a concentrated aqueous solution of HCl until pH 2 and extracted with EtOAc (2×100 mL). The combined organic layer were dried (MgSO4) and concentrated under vacuum to afford the title compound as a yellow solid (3.46 g, 87%). HPLC (Method A) Rt 3.77 min (purity 96.1%).
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:8]2)=[CH:3][CH:2]=1.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][C:32]#[CH:33])[CH3:29]>CCCCCCC.CCOC(C)=O>[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][C:32]#[C:33][C:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:27])=[CH:6][CH:5]=2)[N:8]=1)[CH3:29]
Reactant: C#CCN(CC)CC
Reactant: Cc1ccc(-n2nc(OS(=O)(=O)c3ccc(C)cc3)c3cccnc32)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCN(CC)CC#Cc1nn(-c2ccc(C)cc2)c2ncccc12

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-p-tolyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 4:6; yield (64 mg, 40%); 1H NMR δ (CDCl3): 8.64 (m, 1H), 8.19 (m, 1H), 8.11 (d, J=8.52 Hz, 2H), 7.33 (d, J=8.49 Hz, 2H), 7.21-7.28 (m, 1H), 3.86 (s, 2H), 2.73 (q, J=7.17 Hz, 4H), 2.40 (s, 3H), 1.20 (t, J=7.16 Hz, 6H); LCMS m/z: 318.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)[CH:5]=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:7]=1I.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[CH2:22]([O:21][C:19]([C:15]1([C:4]2[CH:5]=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:7]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=3)=[C:2]([Cl:1])[CH:3]=2)[CH2:18][CH2:17][CH2:16]1)=[O:20])[CH3:23]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C1(c2cc(Cl)c(I)c(OCC(F)(F)F)c2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCC1
Yield: 25.7 %

Procedure:
A mixture of ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.35, 7.35 mmol), 4-trifluoromethylphenylboronic acid (0.277 g, 1.47 mmol), CsF (0.277 g, 1.83 mmol) and Pd (PPh3)4 (0.084 g, 0.36 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 20 mL of EtOAc and 20 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate (0.182 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:7][CH:6](OC)[NH:5][C:4]1=[O:10].[C:13]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:19][C@H:18]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[CH:32]1)(=[O:15])[CH3:14]>C1C=CC=CC=1.CC(C)=O>[C:13]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:19][C@H:18]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH:36][CH:6]3[NH:5][C:4](=[O:10])[C:3]([O:2][CH3:1])([O:11][CH3:12])[CH2:7]3)[C:34]=2[N:33]=[CH:32]1)(=[O:15])[CH3:14]
Reactant: COC1CC(OC)(OC)C(=O)N1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: COC1(OC)CC(Nc2ncnc3c2ncn3[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)NC1=O
Temperature: 160 °C
Yield: 73.4 %

Procedure:
3,3,5-Trimethoxy-2-pyrrolidinone (445 mg) was evenly admixed with adenosine 2',3',5'-triacetate (1 g) and the mixture was melted and reacted by heating at 160° C. for 2 hours. The reaction mixture was then allowed to cool and subjected to silica gel column chromatography using benzene-acetone (2:1) as the eluent to give N6 -(3,3-dimethoxy-2-oxo-5-pyrrolidinyl)adenosine 2',3',5'-triacetate (1 g). This product was dissolved in ammonia-saturated methanol (30 ml) and left standing at 5° C. for 17 hours, after which time it was concentrated under reduced pressure. The residue was washed with benzene and the insolubles were subjected to silica gel column chromatography using chloroform-methanol (10:1) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give crystals. Recrystallization from methanol-acetone yielded N6 -(3,3-dimethoxy-2-oxo-5-pyrrolidinyl)adenosine as colorless crystals (680 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(O)C.[N+:14]([C:17]1[C:22]([CH:23]=O)=[CH:21][C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)([O-:16])=[O:15].C(O)(=O)C>C(Cl)(Cl)Cl>[N+:14]([C:17]1[C:22]([CH:23]=[C:6]2[CH2:7][O:8][CH2:9][CH2:10][N:5]2[CH2:4][CH2:3][CH2:2][NH2:1])=[CH:21][C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)([O-:16])=[O:15]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: NCCCN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C=C2COCCN2CCCN)c([N+](=O)[O-])cc1OC
Yield: 94.1 %

Procedure:
A solution of N-(γ-aminopropyl)morpholine (63 g, 0.44 mole) and ethanol (50 ml) was introduced to a heated suspension of 6-nitroveratraldehyde (84 g, 0.4 mole), ethanol (600 ml) and acetic acid (1 ml). The resulting solution was refluxed for 1.5 hrs and allowed to cool overnight. The solvent was stripped leaving a dark oil which was dissolved in chloroform (300 ml) and washed with water. The chloroform was stripped giving 127 g (95%) of the product.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1.Br[C:13]1[S:14][C:15]([C:19]2[C:20]([CH3:34])=[N:21][N:22]3[C:27]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:26][C:25]([CH3:33])=[N:24][C:23]=23)=[C:16]([Br:18])[N:17]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[Br:18][C:16]1[N:17]=[C:13]([C:11]2[N:7]([CH3:6])[N:8]=[CH:9][N:10]=2)[S:14][C:15]=1[C:19]1[C:20]([CH3:34])=[N:21][N:22]2[C:27]([CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:26][C:25]([CH3:33])=[N:24][C:23]=12
Reactant: Cn1cncn1
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3Br)c(C)nn12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Br)c(C)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
Under nitrogen atmosphere, add n-butyl lithium (2.5 M in hexane, 0.6 mL, 1.5 mmol) to a solution of 1-methyl-1,2,4-triazole (124.5 mg, 1 5 mmol) in THF (3 mL) at −78° C. and stir for 30 min. Add anhydrous zinc chloride (409 mg, 3 0 mmol), continue stirring for 30 min, warm up to room temperature and stir for 2 h. Add 3-(2,4-dibromo-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (229 mg, 0.5 mmol), followed by tetrakis(triphenylphosine)palladium (58 mg, 0.05 mmol) and reflux overnight. Cool to room temperature, dilute with ethyl acetate, and wash with saturated ammonia chloride. Dry the organic portion over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes:ethyl acetate (10:2.5) to give the title compound as a yellow foam (77 mg). MS (APCI) m/z (79Br) 460.4 (M+1)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.CCCCN1C=[N+](C)C=C1>[Zn]>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][C:15]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cccc(C)c1
Agent: CCCCn1cc[n+](C)c1
Agent: [Zn]
Product: Cc1ccc(C(=O)c2ccccc2)c(C)c1
Temperature: 25 °C

Procedure:
Benzoic acid (0.31 g, 2.5 mmol), m-xylene (0.53 g, 5.0 mmol), [bmim] [NTf2] (0.50 g) and M(NTf2)2 (M=Co (0.14 g, 0.25 mmol), or Zn (0.15 g, 0.25 mmol) were placed in flasks equipped with stirrers and condensers. The contents of the flask were heated under reflux (ca 140-150° C.) for 2 days, then cooled to room temperature. The products were analysed by gas chromatographic analysis and found to give 93 and 87% conversions (for Co and Zn bis-triflimide reactions respectively) to 2,4-dimethylbenzophenone and, it is believed to be, 2,6-dimethylbenzophenone (11:1 isomer ratio in both cases). The results show that Zinc and cobalt bis-triflimide have been found to catalyse the benzoylation of m-xylene with benzoic acid. The reaction is slower that the corresponding reaction with benzoyl chloride. The catalyst was recycled and the reaction was repeated. The results of the repeat experiment are shown in Table 4.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23].O1CCCC1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[N:11]([C:22](=[O:23])[CH2:21][Cl:20])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1
Reactant: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1ccc(N(C(=O)CCl)c2c(F)c(F)cc(F)c2F)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
N-(2′,3′,5′,6′-tetrafluorophenyl)-4-ethylanilin (2.05 g) and chloro acetylchloride (1.99 g) is mixed without solvent and heated with stirring to 90° C. under nitrogen for 20 h. Tetrahydrofurane (10 ml) and aqueous sodium bicarbonate are added after cooling and stirring is continued for about 1 hour. The organic phase is diluted with toluene and washed with water three times and dried over magnesium sulfate. Evaporation and chromatography of the residue (silica, toluene) gave N-(2′,3′,5′,6′-tetrafluorophenyl)-N-chloroacetyl-4-ethylaniline (1.84 g) as a solid which is recrystallised from heptane, mp.: 72° C.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1COCCN1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCOCC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and morpholine as starting raw materials, to produce an intended compound.