Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:13])[CH2:6]P(OC)(OC)=O.[CH3:14][C:15]1([C:20]2([CH:23]=O)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17][O:16]1>C1COCC1>[CH3:3][O:4][C:5](=[O:13])/[CH:6]=[CH:23]/[C:20]1([C:15]2([CH3:14])[O:16][CH2:17][CH2:18][O:19]2)[CH2:21][CH2:22]1
Reactant: CC1(C2(C=O)CC2)OCCO1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/C1(C2(C)OCCO2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3 g of sodium hydride suspension (60% in paraffin oil) is introduced into 750 ml of THF, cooled under nitrogen to 0° C., and 10.9 g of dimethylphosphonoacetic acid methyl ester is added. Then, 7.5 g of aldehyde 7 is added in drops to 15 ml of THF, and it is stirred at room temperature for 2 hours. It is now quenched carefully with sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 9.5 g of title compound 93 accumulates as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:8]([C:11]#[N:12])=[N:9][CH:10]=1)=[O:5])C.[OH-:21].[K+].Cl>CCO.O>[C:11]([C:8]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]([C:4]([OH:3])=[O:5])=[CH:10][N:9]=1)(=[O:21])[NH2:12]
Reactant: CCOC(=O)c1cnc(C#N)n1COCC[Si](C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(C(=O)O)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-cyano-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carboxylic acid ethyl ester (prepared in the previous step)(0.28 g, 0.95 mmol) in 10 mL of 50% EtOH/H2O was added a 2 N KOH soln (0.95 mL, 1.9 mmol) and the mixture stirred for 8 h at RT. The pH was adjusted to 4 with 3 N HCl and the ppt was collected and dried to give 0.24 g (88%) of a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 13.39 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 6.29 (s, 2H), 3.57 (t, J=7.8 Hz, 2H), 0.87 (t, J=7.8 Hz, 2H), 0.00 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C11H19N3O4Si, 286.1 (M+H), found 285.8.
Reaction SMILES: O.NN.[F:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[N:11]1C(=O)C2=CC=CC=C2C1=O.[ClH:22]>O1CCOCC1>[ClH:22].[F:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH2:11]
Reactant: O=C1N[C@H](CF)[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: C1COCCO1
Solvent: O
Product: N[C@@H]1C(=O)N[C@@H]1CF
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
14 ml of a solution of 1 ml of hydrazine hydrate in 50 ml of dioxane were added to a suspension of 1.24 g of the product of Step D in 1.2 ml of dioxane and the mixture was stirred at room temperature for 45 minutes and 5 ml of N hydrochloric acid were added thereto. The mixture was stirred for 15 hours and was evaporated to dryness. The residue was added to water and 2.3 ml of N hydrochloric acid with stirring and the mixture was filtered. Ethanol was added to the filtrate and the mixture was evaporated to dryness. Methanol was added to the residue followed by ethanol addition and the mixture was evaporated to dryness. The product was crystallized from methanol to obtain 0.391 g of cis 4-fluoromethyl-3-amino-2-oxo-azetidine hydrochloride melting at ≃220° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]>>[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:20][C:12](=[O:14])[C@H:10]([CH3:11])[NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure D and using N-(3,5-dichlorophenyl)-D,L-alanine and L-phenylalanine methyl ester hydrochloride (Sigma), the title compound was prepared. The reaction product was purified by silica gel chromatography using 50% ethyl acetate/hexane.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14]O)[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].O=S(Cl)[Cl:31]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][Cl:31])[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]
Reactant: OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Fc1cccc(F)c1Cn1c(-c2c(F)cccc2F)nc2c(CCl)cccc21
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxylmethyl-benzimidazole (Example 112) (0.54 g, 1.40 mmol) dissolved in CHCl3 (3.0 mL) was added SOCl2 (0.15 mL, 2.06 mmol, 150 M %). After 3 h at room temperature, the reaction was diluted with CHCl3, and washed with NaHCO3 (sat. soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography eluting with 1% MeOH/CH2Cl2. Recrystallization from diethylether:hexane (3:1) yielded white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-chloromethylbenzimidazole (0.52 g, 1.28 mmol, 92% yield). M.p. 143-144° C. 1H-NMR (300 MHz, CD2Cl2): δ 7.55 (m, 1H, H4′), 7.48 (dd, J=7.7, 1.1 Hz, 1H, H7), 7.36 (dd, J=7.6 Hz, 1.1 Hz, 1H, H5), 7.30 (dd, J=7.7, 7.6 Hz, 1H, H6), 7.25 (m, 1H, H4″), 7.09 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.36 (s, 2H, CH2PhF2), 5.07 (s, 2H, CH2Cl).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].Cl>C(O)C>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Yield: 52 %

Procedure:
A mixture of 25.26 g (0.0818 mole) 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 15.35 g (0.0900 mole) of 4-amino-3-methoxy-benzoic acid, 300 mL of ethanol and 1200 mL of 1M hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 18.7 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-38) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:19])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:19])[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CCC2(CC1)OCCO2
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc(F)c(F)c2)CC1
Yield: 62 %

Procedure:
A solution of 8-(3,4-difluorophenyl)-1,4- dioxaspiro[4.5]decan-8-ol (5.4 g, 20 mmole) in acetone-1N hydrochloric acid (1:1) was stirred for 4 hr. The acetone was removed in vacuo and the crude material crystallized from isopropyl ether to give the product (62%, mp: 84°-85° C.).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][CH2:13][SH:14].[H-].[Na+]>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([S:14][CH2:13][CH3:12])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1nc(Cl)ccc1[N+](=O)[O-]
Reaction time: 2.25 h
Yield: 52.8 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (2.24 g, 11.6, 1.0 eq.) and EtSH (0.86 mL, 11.6 mmol, 1.0 eq.) in THF (60 mL) under nitrogen at 0° C. was added NaH (95%; 0.33 g, 13.1 mmol, 1.1 eq.). After 2.25 hr, the solution was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water, saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using hexanes:EtOAc (10:0.05) as eluent afforded 6-chloro-2-(ethylthio)-3-nitropyridine as a yellow solid (1.34 g, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[OH:26])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7].[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7]
Reactant: CCN(CC)CCCCl
Reactant: COc1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)ccc1O
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1OC

Procedure:
Reaction of 3-(3-methoxy-4-hydroxybenzoyl)-2-phenylbenzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:44]1[CH:48]=[CH:47][N:46]=[C:45]1[C:49](Cl)=O>CN(C=O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([CH2:10][C:9]2[C:8](=[O:21])[C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:49]=2[C:45]2[O:44][CH:48]=[CH:47][N:46]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Reactant: O=C(Cl)c1ncco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2c(-c3ncco3)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 2.6 %

Procedure:
Separately, in a 100 mL round-bottomed flask, methyl 4-(3-(4-chloro-2-(phenylamino)phenyl)-3-oxopropyl)benzoate (898 mg, 2.28 mmol) was combined with THF to give a yellow solution. A 1.0 M solution of NaHMDS in THF (5.7 ml, 5.7 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. A heterogeneous mixture of oxazole-2-carbonyl chloride from above, THF (5 mL), DMF (500 μL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. The reaction flask was cooled to 0° C., then the reaction was quenched with water. The resulting heterogeneous mixture was extracted with ethyl acetate, and the organic phase was dried over MgSO4, filtered, then concentrated. The crude product was dissolved in methylene chloride, then concentrated over silica gel. The silica gel supported crude product was loaded onto a 80 gram analogix column. Flash chromatography (15% EtOAc-hexanes→55% EtOAc-hexanes) provided 4-(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-benzoic acid methyl ester (28 mg, 2.6%) as a light yellow solid.
Reaction SMILES: [OH-].[Li+].O.C([O:6][C:7](=[O:19])[C:8]1[C:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[OH-].[Na+]>C1COCC1>[CH:14]1([C:13]2[C:8]([C:7]([OH:19])=[O:6])=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)c1ccccc1C1CCCC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C1CCCC1
Reaction time: 5 h

Procedure:
0.200 g (8.35 mmol) lithium hydroxide and 15 mL water were added to a solution of 1.10 g (5.04 mmol) 6-cyclopentyl-benzoic acid ethyl ester in 20 mL THF at RT, and the resulting mixture was stirred over night. 5.00 mL (20.0 mmol) 4 M aqueous NaOH solution were added and stirring was continued at 50° C. for 5 h. THF was removed by distillation. The residue was acidified with 4 M aqueous hydrochlorid and the precipitate was filtered off, washed with water and dried.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:26])[CH2:7][CH2:8][N:9]([C:23](=[O:25])[CH3:24])[CH:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)C>C(O)C.O>[C:23]([N:9]([CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][C:6]([OH:26])=[O:5])(=[O:25])[CH3:24]
Reactant: CCOC(=O)CCN(C(C)=O)C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N(CCC(=O)O)C1c2ccccc2-c2ccccc21
Reaction time: 4.5 h
Yield: 42.3 %

Procedure:
1.6 ml of 1N sodium hydroxide was added dropwise to a solution of 435 mg of N-acetyl-N-(9-fluorenyl)-β-alanine ethyl ester in 25 ml of ethanol under ice-cooling. After stirring for 4.5 hours, the reaction solution was condensed. The residue was dissolved in water and, then, washed with ether. The pH value of the water layer was adjusted to 3 to 4 with 5% hydrochloric acid. The precipitate formed was separated by filtration, washed with ice-cold water, and recrystallized from a mixture of ethyl acetate and methanol to give 168 mg of N-acetyl-N-(9-fluorenyl)-β-alanine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH2:12][CH2:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:14][C:15]1[O:20][C:18](=[O:19])[CH2:17][CH:16]=1>C1(C)C=CC=CC=1>[CH2:16]([C:17]1[C:18](=[O:19])[NH:10][CH2:11][CH2:12][CH2:13][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:15]([CH3:14])=[O:20]
Reactant: CC1=CCC(=O)O1
Reactant: COc1cccc(C2=NCCC2)c1
Solvent: Cc1ccccc1
Product: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The solution of 70 g of 2-(3-methoxyphenyl)-1-pyrroline [J. Org. Chem. 23, 1278, 1281 (1958)] and 43.2 g of α-angelicalactone in 600 ml of toluene is refluxed overnight. A second portion of 43.2 g of α-angelicalactone is added, the mixture is again refluxed overnight, cooled and evaporated. The residue is crystallized from 50 ml of ethyl acetate, to yield the 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, melting at 140°-142°.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([N:20]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][C:22]([CH:32]=O)=[N:21]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([N:20]1[C:24]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:23][C:22]([CH2:32][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[N:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: Cc1ccc(-c2cc(CNCCN3CCN(c4ccccc4)CC3)nn2C(C)(C)C)cc1
Yield: 80 %

Procedure:
Compound 10 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.C1(C)C=CC(S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O)=CC=1.Cl>O.CN(C)C=O>[F:27][C:26]([F:29])([F:28])[CH2:25][S:14][C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=1
Reactant: Oc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(SCC(F)(F)F)cc1
Reaction time: 3 h
Yield: 80.8 %

Procedure:
With stirring in an atmosphere of nitrogen, 110 g of anhydrous potassium carbonate was added to a solution composed of 51 g of 4-hydroxybenzenethiol and 250 ml of dimethylformamide. Furthermore, 112 g of 2,2,2-trifluoroethyl p-toluenesulfonate was added at a temperature of 25° to 30° C. The mixture was stirred at the same temperature for 3 hours, then at 30° to 40° C. for 4 hours, and finally at 50° C. for 6 hours. After cooling, the solution was poured into 2 liters of water, and concentrated hydrochloric acid was added at a temperature lower than 20° C. to adjust the pH of the solution to 3. The resulting oily product was extracted with toluene. The toluene layer was washed with water, and stirred together with 600 ml of a 10% aqueous solution of potassium hydroxide. The aqueous layer was separated, and hydrochloric acid was added at a temperature lower than 20° C. to adjust the pH of the aqueous layer to 2. The resulting oily product was extracted with toluene. The toluene layer was separated, washed with water, and then dried over anhydrous sodium sulfate. The toluene was evaporated, and the residue was distilled under reduced pressure to give 68 g of the desired 4-(2,2,2-trifluoroethylthio)phenol. b.p. 102°-105° C./0.8 mmHg.
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([OH:15])[CH2:10]2.[CH2:21]=O.[ClH:23]>C(O)C>[ClH:23].[CH:18]([N:17]1[CH2:16][CH:2]([CH2:3][O:4][C:5]2[C:6]3[CH2:7][CH2:8][CH:9]([OH:15])[CH2:10][C:11]=3[CH:12]=[CH:13][CH:14]=2)[O:1][CH2:21]1)([CH3:20])[CH3:19]
Reactant: C=O
Reactant: CC(C)NCC(O)COc1cccc2c1CCC(O)C2
Agent: Cl
Solvent: CCO
Product: CC(C)N1COC(COc2cccc3c2CCC(O)C3)C1

Procedure:
A solution of 5.58 g. (0.02 mole) of 1,2,3,4-tetrahydro-5-[2-hydroxy-3-(isopropylamino)propoxy]-2-naphthol in 30 ml. of 99% ethanol is treated with 4 ml. of 33% formalin and heated under reflux for 12-16 hours. The solution is acidified with hydrochloric acid in ethanol and the oxazolidine hydrochloride precipitated by the addition of ether.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([O:7]CC)=O)=[O:2].[CH:10]1([C:13](=[N:15]O)[NH2:14])[CH2:12][CH2:11]1>CCO>[CH:10]1([C:13]2[N:15]=[C:5]([CH2:4][NH:3][CH:1]=[O:2])[O:7][N:14]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)CNC=O
Reactant: NC(=NO)C1CC1
Solvent: CCO
Product: O=CNCc1nc(C2CC2)no1
Temperature: 25 °C

Procedure:
A solution of ethyl formylaminomethyl-carboxylate (150 mmol) and cyclopropyl carboxamide oxime (100 mmol) in 100% EtOH (100 ml) was charged with Na (200 mg) and crushed molecular sieve (4Å) (10 g). The mixture thus obtained was stirred and heated to reflux for 8 hours. The mixture was cooled to room temperature, filtered through filter aid and the filtrate was evaporated in vacuo. The oily residue was partitionated into a CHCl3 phase which was dried with Na2SO4 and evaporated.
Reaction SMILES: [O:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:5]1[C:4]2[CH:3]=[CH:2][O:1][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2c2occc12
Product: Clc1nc2ccccc2c2occc12

Procedure:
First, the known compound 5H-furo[3,2-c]quinolin-4-one (compound 1) is reacted with POCl3 to produce 4-chlorofuro[3,2-c]quinoline (compound 2). Compound 2 is further reacted with 3-aminoacetophenone in a solution of EtOH-H2 (2:1) to yield 1-[3-chlorofuro[3,2-c]quinolin-4-ylamino]phenyl)ethanone (compound 3).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]([N:19]=[C:20]=[S:21])([CH3:18])([CH3:17])[CH3:16].O>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[S:21])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)N=C=S
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NC(=S)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
24.93 g of 4-amino-1-benzylpiperidine are dissolved in 300 ml of dichloromethane and then 16.7 ml of tert-butylisothiocyanate are added dropwise and at room temperature. The reaction mixture is stirred at room temperature for 5 hours and then water is added and the mixture is allowed to settle. The organic phase is separated, dried over sodium sulphate and evaporated. The residue obtained is crystallized from petroleum ether in order to give white crystals which melt at 137° C.; yield: 88%.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)=[O:2].[CH2:21]([Mg]Br)[CH2:22][CH3:23]>>[OH:2][CH:1]([C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCC[Mg]Br
Reactant: N#C/C=C1\c2ccccc2CCc2cc(C=O)ccc21
Product: CCCC(O)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Yield: 63.8 %

Procedure:
[step 1] Using (E)-(2-formyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (245 mg, 0.95 mmol) obtained in Example 83, step 1, and propylmagnesium bromide (2.0 mol/L THF solution; 0.71 mL, 1.42 mmol) instead of methylmagnesium chloride, and in the same manner as in Example 83, step 2, (E)-[2-(1-hydroxybutyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (184 mg, 64%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:20])=[O:19]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COS(C)(=O)=O)O1

Procedure:
The (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (Aldrich, 0.38 mL, 3.1 mmol), triethylamine (0.85 mL, 6.1 mmol), and methanesulfonyl chloride (0.31 mL, 4.1 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25]>CS(C)=O.O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 80 °C

Procedure:
44.5 g (280 mmol) of 3-bromopyridin-2(1H)-one are dissolved in 750 ml of anhydrous dimethyl sulfoxide and admixed at room temperature with 33.4 g (298 mmol) of potassium tert-butoxide in portions. The suspension is stirred at this temperature for 1 h, before 38.5 g (280 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are added and the reaction solution is heated to 80° C. for 20 h. It is allowed to cool and diluted cautiously with water. The precipitated crystalline solid is filtered off, washed with a little water and dried under reduced pressure. This affords 62 g (80% of theory) of the desired product.