Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=1.[N:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1>C1COCC1>[N:21]1[CH:26]=[CH:25][C:24]([C:27]([C:16]2[S:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([F:6])([F:19])[F:20])=[CH:13][CH:12]=3)=[N:18][CH:17]=2)([OH:29])[CH3:28])=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccncc1
Reactant: FC(F)(F)c1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78556.6 %

Procedure:
To a stirred solution of DIPA (0.09 mL, 0.000655 mmol) in THF (7 mL) at −78° C. was added n-BuLi (0.54 mL, 0.000873 mmol) and the mixture stirred at 0° C. for 30 min. After the reaction mixture was cooled to −78° C., a solution of 2-(4-(trifluoromethyl)phenyl)thiazole (0.1 g, 0.000436 mmol) in THF (2 mL) was added dropwise over 30 min. 1-(Pyridin-4-yl)ethanone (0.05 mL, 0.000480 mmol) in THF (2 mL) was then added and the reaction mixture was stirred for an additional 1 hour at −78° C. The work up and purification was done as described in Example 23, Step 2, to provide 1-(pyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethanol (0.12 g, 80%) as off-white solid in 99% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.52 (dd, 2H), 8.07 (d, 2H), 7.90 (s, 1H), 7.80 (d, 2H), 7.50 (dd, 2H), 6.71 (s, 1H), 1.94 (s, 3H); LC-MS m/z calculated for [M+H]+351.07. found 351.1.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:10]=[C:9]([OH:19])[N:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:20]N1C(=O)CCC1=O>CN(C)C=O>[Br:20][C:12]1[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][C:9]([OH:19])=[N:10][C:11]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCc1cc(CCCCCC)nc(O)n1
Solvent: CN(C)C=O
Product: CCCCCCc1nc(O)nc(CCCCCC)c1Br
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 20.3 %

Procedure:
4,6-dihexylpyrimidin-2-ol (31.2 g, 118 mmol) was dissolved in 375 mL of dimethylformamide, and 21.0 g (118 mmol) of N-bromo-succinimide was added at 3° C., and the mixture was stirred for 2.5 hours. Ice water (500 g) was added, and the mixture was extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate and concentrated. The concentrate was purified by re-crystallization from ethanol, and the purity thereof was enhanced by a silica gel column (hexane•ethyl acetate) to obtain 8.4 g (24 mmol) of 5-bromo-4,6-dihexylpyrimidin-2-ol.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]2[S:3]1>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
Zinc powder (0.9 g) was added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (0.69 g), mp 120° to 130° C., in a mixture of dimethylformamide (5 ml) and acetic acid (1 ml), and the mixture was stirred for 1.5 hours, followed by filtration of the reaction mixture, after which the filtered zinc was washed with a small amount of dimethylformamide. The filtrate and the washings were combined and the combined solution was poured into a mixture of ethyl acetate (30 ml), water (30 ml) and 10% hydrochloric acid (2 ml), after which the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate (10 ml). The ethyl acetate layer was combined, and the combined solution was in turn washed with water, a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after which the solvent was distilled off. The residue was crystallized by adding a small quantity of acetonitrile, and the precipitated crystals were collected by filtration and dried to give 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid (0.34 g), mp 121° C., which is an isomer at 2 position of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid, mp 109° C. (dec.), which was obtained in Example 19.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[F:30][C:29]([F:31])([F:32])[C:20]1[CH:21]=[C:22]([C:25]([F:28])([F:26])[F:27])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccc(C(F)(F)F)cc3C(F)(F)F)ccc12
Yield: 22.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 454 using 70 (121 mg, 0.57 mmol) and 1-(bromo-methyl)-2,4-bis(trifluoromethyl)benzene (176 mg, 0.57 mmol) to provide 455 (55 mg, 22% yield) as a white powder. LC-MS (M+H=438, obsd.=438). 1H NMR (400 MHz, DMSO-D6) δ 11.55 (s, 1H), 8.37 (m, 2H), 8.06 (dd, J=7.9, 13.0, 2H), 7.84 (d, J=8.5, 1H), 7.31 (m, 2H), 7.24 (dd, J=4.7, 7.9, 1H), 6.94 (dd, J=2.1, 8.8, 1H), 4.77 (d, J=5.7, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([CH:28]=[CH:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([CH:28]=[CH:29][CH:30]3[CH2:35][CH2:34][N:33]([C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:10])[CH2:32][CH2:31]3)(=[O:26])=[O:27])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=S(=O)(C=CC1CCNCC1)N1CCN(c2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CCC(C=CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Reaction time: 3 h

Procedure:
3-Phenylpropionyl chloride (0.21 ml) was added dropwise to a solution of 4-(4-fluorophenyl)-1-[2-(piperidin-4-yl)-ethenylsulphonyl]-piperazine (0.5 g) in dichloromethane containing triethylamine (0.2 ml). The mixture was stirred for 3 hours, evaporated to dryness, diluted with water and extracted with ethyl acetate (2×15 ml). The ethyl acetate extracts were combined and washed with aqueous sodium bicarbonate, water and dried. Removal of the solvent gave 4-(4-fluorophenyl)-1-[2-(1-phenethylcarbonylpiperidin-4-yl)-ethenylsulphonyl]-piperazine as a gum, M+H=486 (485).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([O:28]CC1C=CC(OC)=CC=1)=[O:27])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=[O:27])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(COC(=O)Cc2ccccc2OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccccc1CC(=O)O
Reaction time: 0.67 h
Yield: 80.3 %

Procedure:
4-Methoxybenzyl 2-(N-CBz-L-valyloxy)phenylacetate (4.25 g, 8.4 mmol), was dissolved in dichloromethane (40 ml). Triflouroacetic acid (8 ml) was added with cooling on ice. The mixture was allowed to reach room temperature and stirred for 40 min. The solvent was removed under reduced pressure and the crude product was recrystallized twice (hexan-ethyl acetate+a small amount of dichloromethane) to give the title compound (2.6 g, 80%). The compound can be activated and esterified to a drug or further modified as described below.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]#[N:9].[NH2:10][OH:11]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8](=[N:10][OH:11])[NH2:9]
Reactant: NO
Reactant: N#CC=Cc1cccs1
Solvent: CO
Product: NC(C=Cc1cccs1)=NO
Reaction time: 8 h

Procedure:
β-(Thien-2-yl) acrylonitrile (2.78 g.) was dissolved in dry methanol (60 ml.) and treated with a solution of hydroxylamine in methanol (60 ml.) (prepared by dissolving hydroxylamine hydrochloride (6 g.), in methanol (60 ml.) and neutralising with sodium methoxide in methanol). The solution was refluxed for 6 hr. and left overnight to cool. Evaporation in vacuo left a brown oil which was dissolved in chloroform and washed with water (10 ml.). The chloroform solution was evaporated to dryness leaving the crude amidoxime, 2.76 g. (80%). Recrystallisation from aqueous methanol gave β-(thien-2-yl) acrylamidoxime, m.p. 92° , λmax. (EtOH) 306 nm, (ε 20070) (Found: C, 49.7; H, 4.7; N, 16.8; S, 18.7. C7H8N2OS requires C, 50.0; H, 4.8; N, 16.7; S, 19.05%).
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH:12]=[CH2:13])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[C:1]1([C@H:7]([CH2:11][CH:12]=[CH2:13])[C:8]([Cl:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC[C@H](C(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC[C@H](C(=O)Cl)c1ccccc1
Reaction time: 2 h

Procedure:
Combine (S)-2-phenylpent-4-enoic acid (1.53 g, 8.7 mmol), dichloromethane (10 mL), and dimethylformamide (1 drop). Add oxalyl chloride (1 mL, 11.46 mmol). After 2 hours, evaporate in vacuo to give (S)-2-phenylpent-4-enoyl chloride. Combine with toluene (10 mL) and add, with vigorous stirring, to a cooled (ice bath) aqueous solution of methylamine (2 mL, 40%). After 1 hour, partition the reaction mixture between water and dichloromethane. Separate the layers, dry the organic over MgSO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with hexane to give a solid. Collect the solid by filtration and dry to give (S)-2-phenylpent-4-enoic acid, N-methyl amide: mp; 97-99° C. Rf =0.53 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28](O)=[O:29])[CH:21]=[CH:22][CH:23]=1.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:28](=[O:29])[CH2:27][NH:26][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=2)=[O:31])=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)CNc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccc(Cl)cc2)c1
Yield: 15.5 %

Procedure:
The procedure used is similar to that described in Example 17, but starting with tert-butyl 2-[(4-chlorophenyl)amino]acetate (1.8 g), 2-[3-(3-methylphenyl)-ureido]acetic acid (1.56 g) and thionyl chloride (0.89 g). The product obtained is purified by chromatography on silica (0.04-0.063 mm) (60 g) contained in a column 2.5 cm in diameter [eluent: cyclohexane/ethyl acetate (80:20 by volume)], using an excess pressure of nitrogen of 40 kPa and collecting 20-cc fractions. Fractions 21 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After crystallisation in acetonitrile, tert-butyl 2-{N-(4-chlorophenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (0.5 g), m.p. 125° C., is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:10]([N:16]=1)=[N:11][CH:12]=[CH:13][C:14]=2[CH3:15])[CH2:4][CH2:5][CH3:6].[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[C:24]([C:39]2[N:43]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:42]=[N:41][N:40]=2)[N:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33]OS(C)(=O)=O)=[CH:29][CH:28]=2)[CH:26]=1)=[O:21])[CH3:18]>CS(C)=O.[Cl-].[Na+].O>[CH2:3]([C:7]1[N:16]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([N:25]3[CH:26]=[C:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH:23]=[C:24]3[C:39]3[N:43]([C:44]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:42]=[N:41][N:40]=3)=[CH:32][CH:31]=2)[C:10]2=[N:11][CH:12]=[CH:13][C:14]([CH3:15])=[C:9]2[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc2nccc(C)c2[nH]1
Reactant: CCOC(=O)c1cc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)n(-c2ccc(COS(C)(=O)=O)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(C(=O)OCC)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
Sodium hydride (10 mg) (60% in oil) was added to a stirred solution of 2-butyl-7-methylimidazo[4,5-b]pyridine (48 mg) in dimethyl sulfoxide (5.0 ml) and the mixture was stirred for 30 minutes at ambient temperature. To this mixture was added a solution of 4-ethoxycarbonyl-1-(4-methanesulfonyloxymethylphenyl)-2-(1-trityl-1H-tetrazol-5-yl)pyrrole (193 mg) in dimethyl sulfoxide (2 ml). The mixture was stirred for 3 hours at ambient temperature and poured into brine. The mixture was extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography to afford 2-butyl-3-[4-[4-ethoxycarbonyl-2-(1-trityl-1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (123 mg) as a colorless viscous oil.
Reaction SMILES: [CH2:1]([C:5]1O[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][N:12]=[CH:11][C:9]=2[N:10]=1)[CH:2]([CH3:4])[CH3:3].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:16]([N:23]1[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][N:12]=[CH:11][C:9]=2[N:10]=[C:5]1[CH2:1][CH:2]([CH3:3])[CH3:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)Cc1nc2cnccc2c(=O)o1
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1nc2cnccc2c(=O)n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-isobutyl-4H-pyrido[3,4-d][1,3]oxazin-4-one (3.0 g, 14.68 mmol) in CHCl3 was added benzylamine (1.73 g, 16.15 mmol) and the reaction was heated to 60° C. After 3 h, the reaction was cooled to room temperature and solvent removed in vacuo. The resulting residue was dissolved in ethylene glycol and sodium hydroxide (0.385 g, 9.62 mmol) was added. The reaction was stirred overnight at 140° C. After cooling to room temperature and extracting with DCM, the organic solution was washed with water. The solution was dried over sodium sulfate and filtered. Concentration of the organic solution provided the title compound as a brown oil. 1H NMR (500 MHz, CDCl3) δ 1.01 (d, J=7 Hz, 6H), 2.33-2.38 (m, 1H), 2.68 (d, J=7 Hz, 2H), 5.43 (s, 2H), 7.16 (d, J=7.5 Hz, 2H), 7.30-7.40 (m, 3H), 8.06 (d, J=5 Hz, 1H), 8.68 (d, J=5 Hz, 1H), 9.13 (s, 1H). MS [M+H] C18H19N3O=294.1.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].C(OCC)(=O)C>CS(C)=O>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][CH2:11]/[C:9](/[CH3:10])=[CH:8]/[CH2:7][CH2:6]/[C:4](/[CH3:5])=[CH:3]/[CH:2]=[O:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Reaction time: 2 h
Yield: 85 %

Procedure:
5 g of the composition prepared in Example 7 are introduced in small fractions over a period of 15 minutes into a solution of 1.6 g of farnesol in 40 ml of dimethyl sulfoxide while maintaining the temperature at from 20° C. to 25° C. After 2 hours under agitation, the solution is poured into 100 ml of hexanes (petrol G) and the precipitate is separated off and washed with water and then with petrol G. The organic phases are concentrated under vacuum and the residue obtained is purified by chromatography over 25 g of R60 Merck® silica in order to separate the remaining stabilizing agent from the farnesal obtained; the eluent is petrol G and then its mixture with ethyl acetate (9/1-v/v). The pure farnesal is isolated with a yield of 85%.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:40][C:41]([CH3:43])=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][N:35]4[CH:41]([CH3:43])[CH3:40])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4)ncn3)cccc2s1
Reactant: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4C(C)C)ncn3)cccc2s1

Procedure:
N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-piperidine-2-carboxamide, Example 49(a), (0.40 g, 0.72 mmol) was reacted with acetone under the conditions of Example 3(d) to give the title compound. MS (ESI, pos. ion.) m/z: 599 (M+1). Mp: 260° C. (with dec.).
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[OH:5][CH2:6][C:7]([CH3:11])([CH2:9][OH:10])[CH3:8]>>[CH3:8][C:7]1([CH3:11])[CH2:9][O:10][P:1]([Cl:4])[O:5][CH2:6]1
Reactant: CC(C)(CO)CO
Reactant: ClP(Cl)Cl
Product: CC1(C)COP(Cl)OC1

Procedure:
For example, Japanese Unexamined Patent Publication No. HEI 2(1990)-273688 (Patent Document 3) discloses that phosphorus trichloride is added to and reacted with neopentyl glycol under ice cooling to obtain 5,5-dimethyl-2-chloro-1,3,2-dioxaphosphorinane.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([NH2:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([NH:17][CH:15]([CH3:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=1)(=[O:4])=[O:3]
Reactant: COc1cccc(CC(C)N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(CC(C)NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (131 g, 1.15 M) was added during 30 min to a solution of 2-(3-methoxyphenyl)-1-methylethylamine (189.7 g, 1.15 M) and triethylamine (116.7 g, 1.15 M) in benzene (2 l) with cooling to maintain an internal temperature of 20°-30°. The reaction was stirred at room temperature for 2 hr. The benzene solution was filtered from the triethylamine hydrochloride. The filter cake was washed with benzene (500 ml) and the combined filtrates were washed with 1 N. HCl (2×250 ml) and water (2×250 ml). The solution was dried over magnesium sulfate and then evaporated to give the sulfonamide as a thick oil. Wt=292 g.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:19])[CH3:18]>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: CC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 56.3 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.69 mmol), acetyl chloride (0.055 mL, 0.69 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (8 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)acetamide (0.10 g). MS (ESI) m/z 258 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[N:27][CH:28]=1>>[CH3:29][C:26]1[N:27]=[CH:28][C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Cc1ccc(O)cn1
Product: Cc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cn1

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 5-hydroxy-2-methylpyridine using dry DME as the reaction solvent: MS (ESI) m/z 404 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH3:5].[H-].[Na+].[CH2:15](Br)[CH2:16][CH2:17][CH3:18].O>C1(C)C=CC=CC=1>[CH2:15]([O:12][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2]([CH3:1])=[CH:3][CH2:4][CH3:5])[CH2:16][CH2:17][CH3:18]
Reactant: CCC=C(C)C(O)CCCCC
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC=C(C)C(CCCCC)OCCCC
Temperature: 80 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
20 g of 4-methyl-3-decen-5-ol dissolved in 100 ml of toluene are added dropwise at 80° C. over a period of 30 minutes to 6.2 g of a 55-60% sodium hydride dispersion in 100 ml of toluene. The mixture is stirred at 80° C. for 12 hours, then cooled to 50° C. and treated dropwise with a solution of 24.1 g of n-butyl bromide in 50 ml of toluene. The mixture is subsequently held at reflux temperature for 6 hours. For the working-up, the mixture is treated at room temperature with water, the organic layer is separated and washed neutral with water, dried and, after the addition of 0.2 g of potassium carbonate, fractionally distilled There are obtained 20.7 g of 5-butoxy-4 methyl-3-decene of boiling point 60° C./0.03 Torr, nD20 =1.4378. Odour: caramel-like, delicate, fatty-fruity.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].O>CN(C=O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCCc2c(O)cccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1CCCCN2CCO
Temperature: 25 °C
Yield: 67 %

Procedure:
1-(2-hydroxyethyl)-6-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine (52 mg) was dissolved in DMF (3 ml), and the resultant solution was stirred at room temperature. Potassium carbonate (122 mg) and methyl bromoacetate (0.035 ml) were added to the solution, and the mixture was stirred at room temperature. After disappearance of the raw materials was confirmed, water (20 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=2/1) to obtain the object compound (47 mg, yield 67%).