Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: OCc1ccccc1
Solvent: O
Product: Cc1ccccc1Cc1ccccc1

Procedure:
3.170 ml of toluene and 10.5 g of bleaching earth (Tonsil K 10 from Sudchemie AG) were heated to boiling in a stirring vessel with a distillation passage, condenser and water separator. 216 g of benzyl alcohol were then passed in through a jet in the course of about 2 hours, i.e. benzyl alcohol was added dropwise under a flow of nitrogen (100 1/h) via an immersed thin tube and in this way was rapidly and uniformly distributed and made to react.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([Cl:20])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>C(Cl)(Cl)Cl>[ClH:20].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Reactant: CC(C)(C)N
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)-c1cc(NC(C)(C)C)nc(=O)n1CC2
Product: Cl

Procedure:
A solution of 9,10-dimethoxy-2-chloro-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one (3.0 g) and tert.-butylamine (10.0 ml) in chloroform (75 ml) is heated under reflux for 16 hours. The solvent is evaporated under reduced pressure and the residue triturated with a dilute solution of sodium hydroxide to give a white precipitate. The precipitate is filtered, dried and converted into its hydrochloride by treating it in solution in ethanol with hydrochloric acid. The hydrochloride is crystallized from ethanol-ether mixture, yield 3.0 g, m.p. 265°-270° C.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.CO.[NH:29]1[CH2:35][CH2:34][CH2:33][C@H:30]1[CH2:31][OH:32]>C(OCC)(=O)C>[C:1]([N:29]1[CH2:35][CH2:34][CH2:33][C@H:30]1[CH2:31][OH:32])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OC[C@@H]1CCCN1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of stearic acid (0.5 g 1.758 mmol) in 5 ml dry pyridine (kept over KOH) (0.399 g, 1.93 mmol) and NHS (0.223 g, 1.93 mmol) were added and dissolved in, stirred for 24 hr at room temperature. Reaction was followed by TLC 5% MeOH. Prolinol (0.197 g, 1.949 mmol) were added and the mixture was stirred at room temperature for three days was added to the mixture, and stirred at room temperature. Reaction controlled by TLC (100% Ethyl acetate). At the end of the reaction, volatiles were removed under reduced pressure and the mixture was dissolved in 30 ml DCM and DCU precipitate was filtrated off and the desired product was purified using column chromatography (ethyl acetate/DCM=1:1).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([CH:16]1[CH2:21][CH2:20][CH:19](Br)[CH2:18][CH2:17]1)[CH2:14][CH3:15]>C(O)C>[CH2:13]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH2:17]1)[CH2:14][CH3:15]
Reactant: CCCC1CCC(Br)CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCC1CCC(C(C(=O)OCC)C(=O)OCC)CC1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
31 g (1.35 mol) of sodium was dissolved in 660 cm3 of anhydrous ethanol, after which 216 g (1.35 mol) of diethyl malonate and then 180 g (0.88 mol) of 4-propylbromocyclohexane were added in single additions, and it was refluxed for 10 hours on a hot water bath. The reactant was cooled to room temperature, and after filtering the NaBr crystals that had formed, the ethanol in the filtrate was removed. Water was added to the residue, it was extracted with chloroform, and washed with water. The chloroform was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 138° C./1.4 mmHg) to obtain 108 g (0.38 mol) of diethyl 4-propylcyclohexylmalonate (trans-cis form mixture).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2C=CN(C)[C:9]=2[S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[Cl:21]S(N=C=O)(=O)=O.[CH3:28][N:29]([CH3:32])[CH:30]=O>C(COC)OC.O>[Cl:21][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]([S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:30][N:29]([CH3:32])[CH2:28]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CN(C)C=O
Reactant: Cn1ccc(-c2ccc(Cl)cc2)c1S(=O)(=O)C(F)(F)F
Solvent: O
Solvent: COCCOC
Product: CN1C=C(S(=O)(=O)C(F)(F)F)C(Cl)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-(p-chlorophenyl)-1-methyl-[(trifluoromethyl)sulfonyl]pyrrole (0.5 g, 0.0015 mol) in dimethoxyethane is treated with chlorosulfonyl isocyanate (0.3 mL, 0.0034 mol), stirred for 24 hours at room temperature, treated with additional chlorosulfonyl isocyanate (0.6 mL, 0.0068 mol), stirred for 24 hours, treated with dimethylformamide (2 mL), stirred for one hour, diluted with water and extracted with ether. The combined organic extracts are washed with water, dried and concentrated in vacuo to obtain a semi-solid. Flash chromatography of the semi-solid using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as a white solid (0.2 g, mp 117°-119° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:19])=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[N:25][C:24](Br)=[CH:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Si:1]([O:8][C:9]1[C:10]([F:19])=[C:11]([C:24]2[N:25]=[CH:26][C:21]([NH2:20])=[N:22][CH:23]=2)[CH:12]=[CH:13][C:14]=1[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)c(F)c1O[Si](C)(C)C(C)(C)C
Reactant: Nc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cnc(N)cn2)c(F)c1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C

Procedure:
(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)boronic acid (292 mg, 1.03 mmol), 2-amino-5-bromopyrazine (179 mg, 1.03 mmol), 1,4-dioxane (6.1 mL), and Na2CO3(2.1 mL, 2 M) were added to a microwave vial and the resultant mixture sparged with argon for 10 minutes. Pd(dppf)Cl2.DCM was then added the mixture, the vial sealed, and then heated at 80° Celsius for 16 hours. The reaction mixture was then cooled to rt, diluted with water (5 mL), and extracted with EtOAc (4×5 mL). The combined organic extracts were then dried over Na2SO4, filtered, and concentrated to dryness to provide the title compound. This compound was used directly in the next synthetic step without purification.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccn(Cc2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
A suspension of 10 g (89 mmol) of uracil and 24.6 g of potassium carbonate in 350 mL DMF was stirred for 12 hours at room temperature, after which 16.5 mL (139 mmol) of benzyl bromide was added and the reaction allowed to continue for 2 days at room temperature. The undissolved residue was removed by filtration and the solvent removed from the filtrate under reduced pressure. 150 mL water was added to the residue and the mixture extracted 3 times with 100 mL methylene chloride. The collected methylene chloride fractions were washed with water, dried over MgSO4 and evaporated to dryness under reduced pressure. The residue was treated with a small amount of chloroform/methanol 40:1 from which 1-benzyluracil partially crystallizes. 2.6 g 1-benzyluracil was isolated by filtration and the rest was isolated by preparative column chromatography, using chloroform/methanol 40:1 giving a yield of 3.95 g (22%)(m.p. 168–170° C., Lit. 168–170° C., Kundu et al., J. Chem. Soc. Perkin Trans 1, 1985, 1295).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Cc1ccc(Oc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(OC[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79 %

Procedure:
4-p-Tolyloxy-phenol (2 g, 9.98 mmol) was taken into anhydrous dimethylformamide (40 mL) and cooled to 0° C. A 60% dispersion of Sodium hydride (0.52 g, 13 mmol) was added portionwise over 10 min. The reaction was kept at 0° C. for 45 min. and then heated to 35° C. for 15 min. (S)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.26 g, 11.9 mmol) was taken into anhydrous dimethylformamide (20 mL) and added to the reaction dropwise over 5 min. The reaction was heated at 75° C. for 12 h. The reaction was quenched with water under nitrogen atmosphere. The mixture was extracted with ethyl acetate (3×). The ethyl acetate was washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography (20:1 silica ratio, eluted with 10% ethyl acetate in hexane) to obtain the title product (3.02 g, 7.88 mmol, 79% yield); MS; m/z 383. found 384 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 1.80 (s, 1H), 1.89-1.92 (m, 3H), 2.26 (s, 3H), 3.27 (s, 2H), 3.86 (s, 1H), 4.00-4.06 (m, 2H), 6.81-6.83 (m, 2H), 6.91-6.98 (m, 4H), 7.13-7.15 (m, 2H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=3)[C:19]3[C:30](=[O:40])[N:31](C(OC(C)(C)C)=O)[CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.Cl>CC(O)C>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]([F:28])[F:29])[CH:26]=3)[C:19]3[C:30](=[O:40])[NH:31][CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cnn(C(F)F)c2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: CC(C)O
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2cnn(C(F)F)c2)c2c(c1F)CNC2=O
Temperature: 75 °C
Reaction time: 3 h
Yield: 20.7 %

Procedure:
tert-Butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (126 mg, 0.998 mmol) was dissolved in 2-propanol (5 mL) and the solution was heated to 75° C. with a heating block. Then 2M HCl (2.5 mL) was added, the temperature was lowered to 65° C., and the reaction mixture was stirred for 3 h. The solution was concentrated and purified by preparatory HPLC eluting with water (10 mM NH4HCO3) and ACN/water (80/20 v/v, 10-50% gradient, 10 mM NH4HCO3) to give the title compound as a white solid (79 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.77 (m, 1 H), 2.09-2.12 (m, 1 H), 3.60-3.63 (m, 1 H), 3.76-3.77 (m, 1 H), 3.88-3.98 (m, 3 H), 4.44 (d, J=6.35 Hz, 2 H), 4.54-4.55 (m, 1 H), 7.17 (d, J=5.86 Hz, 1 H), 7.89 (br s, 1 H), 8.54 (s, 1 H), 8.58 (s, 1 H), 9.43 (s, 1 H). [M+H] calc'd for C16H17F3N6O2, 383; found, 383.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][NH2:38]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([NH:38][CH3:37])=[O:33])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: CNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution of methylamine (1.0 ml in DMF) were combined to give 36 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 512 [M+H]+.
Reaction SMILES: Cl.C(OC(=O)[N:8]([C:15]1[N:19]([CH3:20])[C:18]2[CH:21]=[CH:22][C:23]([N:25]([CH3:43])[C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([S:39](=[O:42])(=[O:41])[NH2:40])[CH:34]=4)[N:27]=3)=[CH:24][C:17]=2[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH3:43][N:25]([C:23]1[CH:22]=[CH:21][C:18]2[N:19]([CH3:20])[C:15]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:16][C:17]=2[CH:24]=1)[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]2[CH:34]=[C:35]([S:39]([NH2:40])(=[O:42])=[O:41])[CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ccc2c(c1)nc(Nc1ccccc1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1

Procedure:
(1-Methyl-5-{methyl-[2-(3-sulfamoyl-phenylamino)-pyrimidin-4-yl]-amino}-1H-benzoimidazol-2-yl)-phenyl-carbamic acid tert-butyl ester hydrochloride was stirred in solution of 50% trifluoroacetic acid and methylene chloride and concentrated to give the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.32 (br s, 1H), 9.54 (br s, 1H), 8.49 (s, 1H), 7.86 (d, J=6.9 Hz, 1H), 7.73-7.78 (m, 3H), 7.47-7.54 (m, 3H), 7.34-7.41 (m, 4H), 7.06-7.14 (m, m 2H), 5.80 (d, J=6.6 Hz, 1H), 3.78 (s, 3H), 3.53 (s, 3H). MS (ESI) m/z=501 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:26]C(OC(C)(C)C)=O)[C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.C(Cl)[Cl:36]>>[ClH:36].[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH2:26])[C:21](=[O:25])[N:22]([CH3:23])[CH3:24])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Reactant: ClCCl
Product: COC(=O)CCc1ccc(Oc2ccc(CC(N)C(=O)N(C)C)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Amide compound 5 (1.8 g) was dissolved in CH2Cl2 (30 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 2 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual sticky solid was dried under vacuum without further purification to yield the crude hydrochloride salt 23 (1.5 g, quantitative yield). 1H NMR (400 MHz, DMSO-d6): 7.20 (overlapped d, J=8.4 Hz, 2H), 7.18 (overlapped d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.50 (m, 1H), 3.55 (s, 3H), 2.98-3.04 (m, 3H), 2.91 (dd, J=14.0 and 8.0 Hz, 1H), 2.80 (t, J=7.2 Hz, 2H), 2.77 (s, 3H), 2.67 (s, 3H), 2.59 (t, J=7.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([CH:17]=[O:18])=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:24](Cl)(=O)[C:25](Cl)=O.[CH3:30]N(C=O)C>C(Cl)Cl.CC(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([CH:17]=[O:18])=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:23])[N:13]=2)=[CH:7][C:3]=1[C:4]([O:6][CH:24]([CH3:25])[CH3:30])=[O:5]
Reactant: CN(C)C=O
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(C=O)c1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2C=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a slurry of 2.5 g of 2-chloro-4-fluoro-5-[4-formyl-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid (Ex. 3) in 50 ml of methylene chloride was added 10 mL of oxalyl chloride followed by catalytic DMF. The solution was stirred for one hour and concd in vacuo. The resultant residue was diluted in 2-propanol and heated to 50° C. for one hour. The reaction was poured onto water and extracted into diethyl ether. The combined organic extracts were washed with brine and 2.5N sodium hydroxide solution, dried and concd to give a material which contained the desired product and a bi-product. Chromatographic purification (silica, 10% ethyl acetate in hexanes) afforded 1.0 g of 2-chloro-4-fluoro-5-[4-formyl-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid, 1-methylethyl ester in a 36% yield: mp 90° C.; 1HNMR (CDCl3) δ 10.04 (s, 1H), 7.9 (d, 1H, J=7.6), 7.25 (d, 1H, J=9.2), 5.23 (m, 1H), 4.11 (s, 3H), 1.35 (d, 6H, J=6.0).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([F:36])[C:29]=1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:29]2[C:28]([F:27])=[CH:33][C:32]([O:34][CH3:35])=[CH:31][C:30]=2[F:36])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1cc(F)c(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)c(F)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 2,6-difluoro-4-methoxyphenylboronic acid, 5-(2,6-difluoro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=30%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH:38]=O)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.[C:40]([O:44][C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])([CH3:43])([CH3:42])[CH3:41]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH2:38][NH:47][C@H:46]([C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:52])[CH2:48][CH:49]([CH3:50])[CH3:51])[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(CC=O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Product: CC(C)C[C@H](NCCc1ccc2c(c1)CN(C(=O)c1cc(C(C)C)c(O)cc1O)C2)C(=O)OC(C)(C)C

Procedure:
Prepared from Intermediate F and L-leucine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 7.31-7.12 (4H, m), 6.38 (1H, s), 3.24-3.04 (2H, m), 2.90-2.69 (4H, m), 1.76-1.56 (1H, m), 1.45 (9H, s), 1.23 (6H, d, J=7.0 Hz), 0.93 (6H, dd, J=10.9, 6.6 Hz). LC/MS: purity >98%, m/z 511 [M+H]+
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:9](O[O:18][C:19](=[O:26])[C:20]1C=CC=[CH:22][CH:21]=1)(=O)[C:10]1C=CC=CC=1.CC(C)=[O:29]>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:19]1(=[O:26])[O:18][C:22](=[O:29])[CH:21]=[CH:20]1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: C=CCCCCC=C
Reactant: CC(C)=O
Product: C=CCCCCCCC=C
Product: O=C1C=CC(=O)O1

Procedure:
This Example shows use alternative dienes to 1,7-octadiene. 1,9-decadiene (55.2 g, 0.40 mol) and maleic anhydride (19.6 g, 0.20 mol) in acetone (200 g) was polymerized in the same apparatus and under the same conditions as Example 4. The yield of desired copolymer was 33.2 g. The 1H NMR showed 17 mole % vinyl octyl protons, 15 mole % saturated octyl protons, and 4.3 mole % phenyl protons from the benzoyl peroxide initiator. Further characterization is presented in Table 2 and in FIG. 2, as discussed below.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)=[O:2].OS(O)(=O)=O.[CH3:19]O>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:19])=[O:12])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(C=O)cc1
Temperature: 5 °C
Yield: 86 %

Procedure:
A suspension of (E)-3-(4-formylphenyl)acrylic acid (2 g, 10.5 mmol) in methanol (30 mL) was cooled to 5° C. and then concentrated H2SO4 (3 mL) was added under stirring and heated at 60° C. for 2 hours. The solvent was removed by evaporation and the obtained compound was stirred with water (100 mL) for 15 minutes. The precipitated white solid was filtered, washed with water (300 mL) and dried to get the pure product (1.9 g, 86% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:9])[C:5](=[O:8])[O:6][CH3:7].[Br:10][CH:11]([CH3:15])[C:12](Br)=[O:13]>>[Br:10][CH:11]([CH3:15])[C:12]([O:1][CH2:2][CH2:3][N:4]([CH3:9])[C:5](=[O:8])[O:6][CH3:7])=[O:13]
Reactant: CC(Br)C(=O)Br
Reactant: COC(=O)N(C)CCO
Product: COC(=O)N(C)CCOC(=O)C(C)Br

Procedure:
by using methyl N-(2-hydroxyethyl)-N-methyl-carbamate and 2-bromopropionyl bromide there is obtained methyl N-[2-(2-bromopropionyloxy)-ethyl]-N-methyl-carbamate, 1H-NMR (CDCl3, 60 MHz) 4.35 ppm (q, 1H), 4.32 ppm (t, 2H), 3.75 ppm (s, 3H), 3.58 ppm (t, 2H), 3.0 ppm (s, 3H), 1.82 ppm (d, 3H);
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[N:1]1([CH2:7][CH2:8][C:9]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(CCN1CCOCC1)NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: c1ccn2c(CCN3CCOCC3)ncc2c1
Temperature: 80 °C
Yield: 78 %

Procedure:
To a solution of 3-morpholin-4-yl-N-pyridin-2-ylmethyl-propionamide (5.4 g, 21.7 mmol) in 1,2-dichloroethane (100 mL), cooled in an ice bath, was added POCl3 (12 mL). The mixture was heated to 80° C. for 3 h. After this time the mixture was allowed to cool and poured slowly into 10% aqueous potassium carbonate (500 mL). The mixture was extracted with dichloromethane (200 mL) and ethyl acetate (200 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine (3.89, 78%).