Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:11]=[N:12]O)[CH:7]=1.C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1
Reactant: COc1cc(Br)cn2ncc(C=NO)c12
Solvent: CC(=O)OC(C)=O
Product: COc1cc(Br)cn2ncc(C#N)c12
Temperature: 50 °C

Procedure:
The oxime isomer mixture of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (85.0 mg, 0.315 mmol) was suspended in acetic anhydride (3.0 ml, 31.8 mmol) and heated to 50° C. for 3 h to give a pale blue solution. The solution was then heated to 75° C. for 2 h to give a dark blue solution. The solution was then heated to 100° C. overnight to give a dark purple mixture. The reaction mixture was concentrated and the residue was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to give 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile.
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([N:11]([CH2:28]C)[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH:24]([OH:26])[CH2:23][C:22]2=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1)C.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][N:11]([CH3:9])[C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:25][CH:24]([O:26][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][C:22]2=[O:27])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCN(CC)c1ccc(S(=O)(=O)N2CC(O)CC2=O)cc1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)c1ccc(S(=O)(=O)N2CC(OC(=O)C(C)(C)C)CC2=O)cc1
Reaction time: 16 h

Procedure:
0.41 g of 1,4-diazabicyclo [2.2.2]octane (DABCO) is added at 3° C. to a solution of 1 g of [1-(4-diethylamino-benzenesulphonyl)-4-hydroxy-pyrrolidin-2-one] in 20 cm3 of methylene chloride, and then 0.43 g of pivaloyl chloride in solution in 3 cm3 of methylene chloride is added slowly, and the whole mixture is left at ambient temperature for 16 hours. Another equivalent of pivaloyl chloride and DABCO is added, the mixture is left at ambient temperature for 4 hours, brought to dryness, the residue is taken up in ethyl acetate, washed with water (at a pH of about 6), followed by filtering and bringing to dryness under reduced pressure, and the residue is chromatographed on silica (eluant: ethyl acetate - hexane 4-1). 0.6 g of expected crude product and 0.3 g of product containing a double bond in position 3,4 of the pyrrolidinone are obtained. The crude product is added to a previous preparation in order to obtain, after recrystallization from an ethyl acetate - hexane mixture (3-50), 0.86 g of the desired product. M.p.=117-118° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([OH:14])[CH2:10][N:11]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([S:7][CH2:8][CH:9]([OH:14])[CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC(O)CSc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)CSc1ccccc1
Yield: 97.1 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 8 g of 3-phenylthio-2-hydroxypropylazide (prepared as described in Preparation 86), 2.9 g of lithium aluminum hydride and 400 ml of anhydrous tetrahydrofuran were used, to give 6.8 g of the title compound, melting at 57° C. to 61° C.
Reaction SMILES: [CH2:1](OC(=O)C(C1C=CC(C)=CC=1)=CN(C)C)C.[CH2:18]([O:20][C:21](=[O:35])[C:22]([C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:23][N:24](C)C)[CH3:19]>>[CH2:18]([O:20][C:21]([C:22]1[CH:23]=[N:24][O:34][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([CH3:1])=[CH:30][CH:29]=1)=[O:35])[CH3:19]
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C)cc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Product: CCOC(=O)c1cnoc1-c1ccc(C)cc1
Yield: 59 %

Procedure:
The procedure of Example 15 was employed utilizing ethyl-2-(4-toluyl)-3-dimethylaminopropenoate in lieu of ethyl-2-benzoyl-3-dimethylaminopropenoate to yield ethyl-5-(4'-methylphenyl)-4-isoxazolecarboxylate (2.03 g.; 59% yield) having a melting point of 42°-44° C. and the following analysis:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:10][C:9](=[O:11])[CH:8]=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccccc1)C=Cc1ccc(O)cc1
Yield: 30.5 %

Procedure:
1-Phenylbut-1-en-3-one (58.4 g), and p-hydroxybenzaldehyde (48.8 g) are dissolved in ethanol (300 ml) and cooled to a temperature below 15° C., using an ice bath. A solution of sodium hydroxide (20 g) in water (80 ml) is added over 2 hours, the temperature of the mixture being kept below 15° C. This solution is then neutralised to pH 7 with dilute hydrochloric acid. An oily solid separates out, and this is filtered and washed with toluene to give 30.5 g of 1-(p-hydroxyphenyl)-5-phenylpenta-1,4-dien-3-one.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15]OC(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([Cl:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)OCl
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Cc2ccccc2)cc1Cl
Yield: 94.3 %

Procedure:
18.4 g of 4-benzylphenol was dissolved in 100 ml of carbon tetrachloride and thereto was added dropwise 10.85 g of t-butyl hypochlorite at -5°-0° C. with stirring. After stirring for 3 hours at room temperature, the reaction mixture was washed with a saturated aqueous sodium hydrogen-carbonate solution and then with water, then dried over anhydrous magnesium sulfate and thereafter, concentrated under reduced pressure. The resulting oily residue was chromatographed on a silica gel column (eluting solvent hexane : acetone=3 : 1 (v/v)) to obtain 20.6 g of 4-benzyl-2-chlorophenol.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:28])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:15][CH:14]([Si](C)(C)C4C=CC=CC=4)[CH:13]([CH2:25][OH:26])[C:12]3=[CH2:27])[C:9]=2[N:10]=1.C(O)(=[O:31])C>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:28])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:15][CH:14]([OH:31])[CH:13]([CH2:25][OH:26])[C:12]3=[CH2:27])[C:9]=2[N:10]=1
Reactant: C=C1C(CO)C([Si](C)(C)c2ccccc2)CC1n1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(=O)O
Solvent: CO
Product: C=C1C(CO)C(O)CC1n1cnc2c(=O)[nH]c(N)nc21
Temperature: 95 °C
Reaction time: 4 h

Procedure:
A 2-L 3-necked round bottomed flask, oven dried and equipped with a mechanical stirrer, an addition funnel, temperature probe, and argon inlet, was charged with compound 71 (34.1 g, 86.2 moles), acetic acid (40.4 mL, 8 eq) and acetic acid-boron trifluoride complex (38 mL). The reaction mixture was heated to 95° C., stirred for 4 hours and then cooled to room temperature. The reaction mixture was diluted with MeOH (200 mL) and quenched with aqueous KOH (10 N, ˜220 mL) to adjust the pH to about 9.5. Potassium bicarbonate (17.9 g) followed by aqueous hydrogen peroxide (30 wt. %, 39 g) was added to the solution. The resulting solution was warmed to 70° C. and stirred for 10 hours. The reaction was cooled to 5–10° C. Sodium bisulfite (16.2 g) was added portion-wise over 30 minutes. The reaction mixture was concentrated in vacuo to remove most of the MeOH. The resulting yellow semi-solid was cooled to −5° C. and concentrated HCl (˜55 mL) added to adjust the pH to 0.15. The resulting solution was extracted with EtOAc (500 mL) and aqueous KOH (10 N, ˜48 mL) added to adjust the pH to ˜11. The solution was stirred for 1 hour and then the pH was adjusted to ˜7 with HCl (4 mL). The reaction mixture was stirred at room temperature for 1 hour and at ˜5° C. for 3 hours. The solid was collected by filtration and dried under high vacuum for 16 hours. The solid was redissolved in water (600 mL) at 90° C. The clear solution was cooled to ˜60–55° C. and seeded with 21. The solution was allowed to cool to room temperature for 5 hours. The resulting white crystalline solid was collected by filtration and dried under vacuum at 50° C. for 16 hours to afford the title compound (12.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:11]([C:10]1[C:9](=[O:14])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:19][N:18]([CH3:20])[CH:17]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)CC(=O)Cc1cccc(Br)c1
Reactant: COC(OC)N(C)C
Product: CC(=O)c1cn(C)cc(-c2cccc(Br)c2)c1=O

Procedure:
To 1.5 g. of 1-(3-bromophenyl)-2,4-pentanedione was added 25 ml. of N,N-dimethylformamide dimethyl acetal. The mixture was stirred at reflux temperature for 18 hours, cooled and evaporated to a thick oil under vacuum. The oil was dissolved in 500 ml. of tetrahydrofuran, and 10 ml. of 40% aqueous methylamine was added. The mixture was stirred at ambient temperature for 4 hours, and was then evaporated under vacuum. The residue was dissolved in 800 ml. of dichloromethane, and washed with 500 ml. of water. The organic layer was dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated under vacuum. The solids were recrystallized twice from dichloromethane/diisopropyl ether. The solids were then chromatographed on a silica gel column with ethyl acetate as the eluting solvent. The yield was 0.8 g. of the desired product, m.p. 192°-194°. Nmr analysis in DMSOd6 showed peaks at δ7.25-8.40 (m, 6H, aromatic); 3.75 (s, 3H, N--CH3); 2.53 (s, 3H, COCH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C:9]1([CH2:10][OH:11])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1(C)CO
Temperature: 80 °C
Reaction time: 6 h
Yield: 62.7 %

Procedure:
To a stirred solution of N-tert-butoxycarbonyl-2-methylproline (1.10 g, 4.80 mmol) in THF (20 mL) was added dropwise BH3-SMe2 (0.546 mL, 5.76 mmol) at room temp. After the resulting mixture was stirred for 6 hr at 80° C., the mixture was evaporated in vacuo. The residue was diluted with MeOH, washed with n-hexane (3×), and evaporated in vacuo to afford 0.648 g (60%) N-tert-butoxycarbonyl-2-hydroxymethyl-2-methylpyrrolidine as a yellow syrup. 1H-NMR (CDCl3) δ 1.47 (s, 9H), 1.76–2.05 (m, 4H), 3.28–3.48 (m, 2H), 3.66 (m, 2H, d).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.C(OCC)(=O)C>[CH2:21]([O:20][C:18]([C:17]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2ccccc2o1
Yield: 33.1 %

Procedure:
A mixture of salicylaldehyde (53.10 g), K2CO3 (97 g) and ethyl bromoacetate (73.30 g) in ethanol (200 ml) was refluxed for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with water, 1N NaOH and brine, dried and concentrated to give the titled compound (27.40 g) as a colorless oil
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1/[CH:4]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(F)c(/C=C/C(=O)O)c1
Yield: 95.8 %

Procedure:
A solution of 2-fluoro-5-methoxybenzaldehyde (10.00 g, 64.9 mmol), malonic acid (13.4 g, 128.8 mmol), piperidine (2.00 mL) and pyridine (100 mL) was heated to 110° C. for 2 h. After this time the solvent was removed in vacuo and the residue taken up in ethyl acetate and washed with aqueous hydrochloric acid (2N, 100 mL). The organic solvent was dried (MgSO4) and the solvent evaporated in vacuo. The solid was recrystallised from hot etahanol to give a white solid (12.2 g, 95%); δH (300 MHz, DMSO) 7.60 (1H, d, J 7 Hz, CH═C), 7.31-7.28 (1H, m, Ar), 7.20 (1H, t, Ar), 7.07-6.97 (1H, m, Ar), 6.62 (1H, d, J 8 Hz, CH═CH), 3.80 (3H, s, OCH3).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:25][C:24](=[O:26])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[N+:27]([CH3:30])([O-:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:25][C:24]([CH2:30][N+:27]([O-:29])=[O:28])([OH:26])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: C[N+](=O)[O-]
Reactant: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CC(=O)C3)n2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CC(O)(C[N+](=O)[O-])C3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-one (1.1 g) in DCM (10 mL) at 20° C. was added nitromethane (1 mL) and triethylamine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. It was concentrated under reduced pressure to afford a white solid. The crude product (1.3 g), 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-3-(nitromethyl)azetidin-3-ol, was used for next step without further purification. MS (ESI) m/z: 407 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH:36]=O)=[CH:30]3)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[CH:36][C:31]3[NH:32][C:33]4[C:29]([CH:30]=3)=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:35][CH:34]=4)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
6-(2-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]([O:23]CC)=[O:22])[N:12]=2)[CH3:10])=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]([OH:23])=[O:22])[N:12]=2)[CH3:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(N(C)c2nc(C(=O)O)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate (560 mg, 1.66 mmol) and sodium hydroxide (126 mg, 3.15 mmol) in 25 mL of methanol and water (1:3) was stirred at room temperature for 5 h. The solvents were removed under vacuum, and the residue was dissolved in 50 mL of water and acidified to pH 3. The white precipitate was collected and washed with water and dried (380 mg, 1.23 mmol, 74%). 1H NMR (CDCl3): 8.02-8.05 (m, 1H), 7.68 (ddd, J=1H, 8.4, 6.9, 1.5), 7.14-7.20 (m, 3H), 7.02-7.05 (m, 1H), 6.94-6.99 (m, 2H), 3.87 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11](=O)[C:12]2[C:17]([CH3:18])=[CH:16][S:15][C:13]=2[N:14]=1.O=P(Cl)(Cl)[Cl:22].CN(C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:22][C:11]1[C:12]2[C:17]([CH3:18])=[CH:16][S:15][C:13]=2[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1nc2scc(C)c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2c(C)csc2n1
Yield: 91.7 %

Procedure:
A solution of 2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.4 g, 1.5 mmol), POCl3 (0.14 mL, 1.5 mmol), and N,N-dimethylaniline (0.29 mL, 2.25 mmol) in benzene (1.7 mL) was heated at 80° C. for 2 h. The reaction was cooled, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum to give 4-chloro-2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine (0.4 g, 91% yield). LC/MS: m/z 291.1 (M+H)+ at 3.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]1.C1C=CC=CC=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C(N(CC)CC)C>[CH2:19]([NH:21][C:22]([O:12][N:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH2:3]1)=[O:23])[CH3:20]
Reactant: ON=C1CCOc2ccccc21
Reactant: CCN=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)ON=C1CCOc2ccccc21
Reaction time: 8 h

Procedure:
4-Chromanone oxime (20 g, 0.12 mole) was added to benzene (260 ml) and refluxed for 45 min. in a flask equipped with a Dean-Stark trap. The solution was cooled to 25°-30°, triethylamine (0.5 ml) was added, followed by ethyl isocyanate (8.5 g, 0.12 mole). The solution was refluxed for 3 hrs. and stored overnight at room temperature. The mixture was filtered and the filtrate was stripped of solvent under reduced pressure. Anhydrous ether (100 ml) was added to the residue and the mixture was cooled for 3 hrs. The product was collected by filtration, yield: 20 g (79%). A sample was recrystallized from isopropanol, m.p. 110°-111°.
Reaction SMILES: BrCCC1C(Cl)=CC(Cl)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1CCBr.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K]>CN(C)C=O>[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:20])[CH:16]=1)[O:12][CH2:5][CH2:6][N:28]1[C:24](=[O:34])[C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]1=[O:29]
Reactant: Clc1cc(Cl)c(CCBr)c(Oc2cc(Cl)cc(Cl)c2CCBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cc(Cl)cc(Cl)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of 101.88 g (0.38 mole) of 2-bromoethyl-3,5-dichlorophenyl ether and b 70.3 g (0.38 mole) of potassium phthalimide in 800 ml of dimethylformamide was stirred overnight at 85° C. The reaction mixture was filtered and dimethylformamide removed from the filtrate in a rotary evaporator to yield a white solid. The solid was triturated with diethyl ether and the mixture filtered. The solid was dried in vacuo. Recrystallized from methylene chloride-hexane, the product melted at 133°-136° C. Yield overall was 41.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.[SH:15][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].C1CCN2C(=NCCC2)CC1.Cl>>[CH3:21][O:20][Si:19]([O:22][CH3:23])([O:24][CH3:25])[CH2:18][CH2:17][CH2:16][S:15][CH:8]([CH:7]1[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=[C:2]1[CH3:1])[CH2:9][C:10](=[O:11])[CH3:12]
Reactant: CO[Si](CCCS)(OC)OC
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CO[Si](CCCSC(CC(C)=O)C1C(C)=CCCC1(C)C)(OC)OC
Reaction time: 2.25 h
Yield: 71.3 %

Procedure:
To a stirred solution of α-ionone (1.92 g, 10.0 mmol) and 3-mercaptopropyl-trimethoxysilane (1.96 g, 10.0 mmol) at 12° C. was rapidly added DBU (0.14 ml, 152 mg, 1.0 mmol). The temperature rose to 19° C. and the solution turned orange. After 135 minutes at 20° C, the reaction mixture was poured onto a cold stirred 5% aqueous HCl solution and extracted twice with Et2O. The organic phases were washed (H2O, saturated aqueous NaHCO3 and brine), dried (Na2SO4), filtered and concentrated. The crude extract was dried for 1 hour at 65-70° C./0.01 Torr to give 2.77 g of the title thioether (71%).
Reaction SMILES: [ClH:1].[O:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=5)[CH:25]=[CH:24][C:23]4=[O:34])[CH2:16][CH2:15]3)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1>[Pd].CO>[ClH:1].[O:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=5)[CH2:25][CH2:24][C:23]4=[O:34])[CH2:16][CH2:15]3)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(c3)OCCO4)CC1)C(=O)CC2
Temperature: 47.5 °C
Reaction time: 8.5 h
Yield: 135.8 %

Procedure:
To 15 mL of a methanol solution containing 0.11 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinolin-2(1H)-one hydrochloride, 50 mg of 10% palladium on carbon was added, and stirred under hydrogen atmosphere at 45-50° C. for 8.5 hours. The insoluble material was filtered off, the solvent was removed under reduced pressure to afford 0.15 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one hydrochloride as a yellow foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.[CH:14]1([C:17]2[N:18]([CH:23]([CH3:25])[CH3:24])[CH:19]=[C:20](I)[N:21]=2)[CH2:16][CH2:15]1>>[CH:14]1([C:17]2[N:18]([CH:23]([CH3:25])[CH3:24])[CH:19]=[C:20]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:21]=2)[CH2:16][CH2:15]1
Reactant: Cc1cc(C#C[Si](C)(C)C)ccn1
Reactant: CC(C)n1cc(I)nc1C1CC1
Product: Cc1cc(C#Cc2cn(C(C)C)c(C3CC3)n2)ccn1

Procedure:
The title compound, MS: m/e=266.3 (M+H+), was prepared in accordance with the general method of example A, step 2 from 2-methyl-4-trimethylsilanylethynyl-pyridine and 2-cyclopropyl-4-iodo-1-isopropyl-1H-imidazole.