Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])C1C=CC=CC=1.[CH3:9][S:10]([C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[OH:23])(=[O:12])=[O:11]>>[OH:23][C:14]1[C:13]([S:10]([CH3:9])(=[O:11])=[O:12])=[CH:18][C:17]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:16][C:15]=1[CH:1]=[O:8]
Reactant: CC(C)(C)c1ccc(O)c(S(C)(=O)=O)c1
Reactant: O=Cc1ccccc1
Product: CC(C)(C)c1cc(C=O)c(O)c(S(C)(=O)=O)c1
Yield: 53 %

Procedure:
The benzaldehyde used in Example 4 was prepared in a similar manner to that described for Example 3. From 7.40 g (32.4 mmol) of 2-methylsulfonyl-4-(1,1-dimethylethyl)phenol (see German Offenlegungsschrift DE 32 08 190 Al to Englert et al, assigned to Hoechst AG as an example of how to obtain this material) there was obtained 4.41 g (17.2 mmol, 53%) of 2-hydroxy-3-methylsulfonyl-5-(1,1-dimethylethyl)benzaldehyde; mp 133°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.C(OC([N:28]1[C:36]2[N:31]([C:32](=[O:38])[N:33]=[C:34](Cl)[CH:35]=2)[CH2:30][C@@H:29]1[CH3:39])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][O:20][C:34]1[CH:35]=[C:36]2[NH:28][C@@H:29]([CH3:39])[CH2:30][N:31]2[C:32](=[O:38])[N:33]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and (S)-tert-butyl7-chloro-2-meth yl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11]([CH3:12])=[O:34])=[N:6]2
Reactant: CSc1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Into a 30 mL vial, 5-Bromo-7-(4-methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.140 g, 0.000351 mol) and Methylene chloride (4 mL, 0.07 mol). m-CPBA 70-75% (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 0.0910 g, 0.000369 mol) was added portion wise over 10 minutes. The reaction was stirred at room temperature for 2 hours. HPLC suggested no starting material. The reaction was partitioned with DCM and NaHCO3. The organic was separated, washed with water, subsequently Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The organic was removed under vacuum to give 5-Bromo-2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (140 mg, 96%). The solid was used as is without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](I)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.[Cl:30][C:31]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:32]=1[OH:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:41][C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:38])([F:39])[F:40])[C:31]=4[Cl:30])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(I)cc1=O
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2cccc(C(F)(F)F)c2Cl)cc1=O
Temperature: 25 °C

Procedure:
A solution of 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Intermediate 94, 51.5 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) at 25° C. was treated with 2-chloro-3-trifluoromethyl-phenol (23.6 mg, 0.12 mmol) and cesium carbonate (65.2 mg, 0.20 mmol). The reaction was stirred at 25° C. over 3 nights. At this time, the reaction was warmed to 80° C. overnight. At this time, the reaction was filtered, rinsed with dimethylsulfoxide (1 mL) and then purified by HPLC chromatography (50-100% acetonitrile/water, C18 Pursuit Agilient, 20×150 mm, 30 ml/min) to afford 2-[4-(2-chloro-3-trifluoromethyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white solid as a mixture of diastereomers (39 mg, 67%); ES+-HRMS m/e calcd for C26H29N5O5F3Cl [M+H+] 584.1882 found 584.1885. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-0.95 (m, 6H), 1.24 (s, 3H), 1.29, 1.30 (2×s, 3H), 1.45 (br. s., 1H), 1.69-1.87 (m, 1H), 1.99-2.32 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 4.00 (dd, J=8.4, 6.2 Hz, 1H), 4.04-4.22 (m, 2H), 4.27-4.43 (m, 1H), 5.53 (dd, J=11.2, 4.2 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 7.70 (t, J=8.2 Hz, 1H), 7.87 (t, J=7.5 Hz, 2H), 8.25 (d, J=2.7 Hz, 1H), 10.85 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.OO.S(=O)(=O)(O)[OH:16]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:16])=[CH:6][CH:7]=1
Reactant: ClCCCSc1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)=O
Product: O=S(CCCCl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 206.76 g (0.44 mol) of 1-chloro-4-[(3-chloropropyl)thio]benzene (J.A.C.S. 82, 2505, 1960) and 111.50 g of 30% H2O2 (0.98 mol) in 1 L of acetone chilled in a dry ice acetone bath was added 90 mL of concentrated sulfuric acid. The ice bath was removed and the mixture stirred at ambient temperature for 16 hr. The mixture was diluted with 1 L of water and extracted with two 500 mL portions of CH2Cl2. The extracts were dried (MgSO4) and concentrated separately and the residual material from both extractions shown to be a mixture of product and starting material. The impure product was chromatographed on Florisil (4×75 cm) using petroleum ether-chloroform for elution. The yield was 50.36 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[N:17]=[CH:18][S:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:33]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[N:17]=[CH:18][S:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nccc3c2)cc1
Temperature: 125 °C

Procedure:
To a solution of 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)isoquinoline-6-sulfonamide (0.10 g, 0.224 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.064 g, 0.292 mmol) and cesium carbonate (0.292 g, 0.897 mmol) in DME (2.437 ml) and Water (0.366 ml) was added Pd(PPh3)4 (0.026 g, 0.022 mmol) in one portion. The resulting mixture was heated to 125° C. in the microwave for 2 hours. The resulting mixture was transferred to a seperatory funnel and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude mixture was purified by the silica gel chromatography (100% hexanes to 25% EtOAc in hexanes to 90% EtOAc in heptanes). m/z (ESI) 586.2 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Br[C:6]([CH3:11])([CH3:10])[C:7](Br)=[O:8].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[C:17]2[C:18]=1[C:7](=[O:8])[CH:6]([CH3:11])[CH2:10]2
Reactant: CC(C)c1cccc(Br)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc(C(C)C)cc(Br)c2C1=O
Temperature: -10 °C

Procedure:
To a mixture of 34.9 g (0.26 mol) of AlCl3 and 350 ml of dichloromethane, a solution of 50.9 g (0.22 mol) of 2-bromo-2-methylpropanoyl bromide in 120 ml of dichloromethane was added dropwise, while vigorously stirring, at −10° C. Then, a solution of 40.0 g (0.20 mol) of 1-bromo-3-isopropylbenzene in 70 ml of dichloromethane was added dropwise at this temperature. The resulting mixture was refluxed for 12 h and then poured onto 2000 cm3 of ice. The organic product was extracted with 4×300 ml of dichloromethane. The combined extract was dried over K2CO3 and evaporated to dryness. Fractional distillation gave the title product, b.p. 130-135° C./1.5 mm Hg. Yield 36.2 g (67%).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C([CH:9]1CCC(C)C[C:10]21[O:15][C:14](=O)[CH:13]=[CH:12][C:11]2=[O:17])(C)C>ClCCl>[CH3:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](=[O:15])[CH2:1][CH2:5][CH:4]=[CH:3][CH3:2]
Reactant: C1=CCC=C1
Reactant: CC1CCC(C(C)C)C2(C1)OC(=O)C=CC2=O
Solvent: ClCCl
Product: CC=CCCC(=O)CCC(=O)CC
Yield: 85 %

Procedure:
In this example, D-A reaction of cyclopentadiene with 7-isopropyl-10-methyloxaspiro(5,5)undec-3-ene-2,5-dione is described. The procedure involves stirring of a mixture of 0.132 g of cyclopentadiene, 0.158 g of 7-isopropyl-10-methyl-oxaspiro(5,5)undec-3-ene-2,5-dione and 0.05 g of sulfated zirconia catalyst doped with scandia prepared according to the procedure similar to that of example 1 above, was stirred in 10 ml of dichloromethane at room temperature for 8 h. The catalyst was filtered off. After evaporation of solvent, the residue was chromatographed over silica gel column by eluting with 5% acetone/petroleum ether to give 0.242 g of spiro{2'-isopropyl-5'methylcyclohexane-1,5,4,oxatricyclo[6.2.1.0.2,7 ]undec-9-ene-3,6 dione} (85% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C1COCC1>[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:1][CH2:2][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=c1cccc(CO)[nH]1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1cccc(=O)[nH]1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.2021 g (1.615 mmol) of the 6-hydroxymethyl-2-pyridone was suspended in 15 mL of THF in a 100 mL RBF under the presence of argon gas and was placed in a −80° C. methanol bath. 1.03 mL (1.648 mmol) of BuLi was added dropwise to the reaction which was stirred for 20 min. 0.4374 grams (1.641 mmol) of 4-iodobenzoyl chloride was dissolved in 15 mL of THF and brought to −80° C. before being added dropwise to the reaction mixture. The reaction was allowed to stir at −80° C. for 48 hours before being warmed to room temperature. The reaction was quenched with 20 mL of water and extracted with ethyl acetate (4×20 mL), the organic layers combined and washed with brine (3×20 mL), and dried over MgSO4. The solvent was removed in vacuo to produce a brown solid. The product was purified by crystallization from toluene. The yield of the reaction was 0.032 g (5.58% Yield). MP: 206-208° C. IR (cm−1) 3426.48 (m, broad), υ (O—H), 3126.38 (m, broad), υ (N—H), 1722.45 (m), υ (C═O), 1656.57 (s), 1392.33 (m) υ (C═C aromatic). 1H NMR (DMSO-d6, 500 MHz) δ: 5.12 (s, 2H), 6.35 (d, J=9.1 Hz, 2H), 7.45 (t, J=7.0 Hz, 1H), 7.76 (d, J=4.8 Hz, 2H), 7.94 (d, J=9.0 Hz, 2H), 11.75 (s, 1H). HRMS: m/e, found 377.9598 (M+Na+). Calc. for C13H10INO3Na: 377.9603.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][N:8]=[C:9]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11].Cl[CH2:19][C:20]([NH2:22])=[O:21]>CS(C)=O>[NH2:22][C:20]([CH2:19][O:7][N:8]=[C:9]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:21]
Reactant: O=C(O)C(=NO)c1ccco1
Reactant: NC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)CON=C(C(=O)O)c1ccco1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of potassium t-butoxide (2.24 g) in dimethylsulphoxide (10 ml) was added a solution of 2-hydroxyimino-2-(fur-2-yl)acetic acid (syn isomer) (1.551 g) in dimethylsulphoxide (10 ml). The mixture was stirred for 30 minutes and a solution of chloroacetamide (0.935 g) in dimethylsulphoxide (10 ml) was added. The mixture was stirred for a further 2 hours, when a clear solution had formed. This solution was poured into ice-water (50 ml) and the mixture was extracted with ethyl acetate. The layers were separated and the aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine and dried, and the solvent was evaporated. The resulting yellow oil was triturated with dichloromethane to give the title compound (0.51 g, 24%), m.p. 143°-145°; λ max (EtOH) 275nm (ε 14,100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8](Cl)=[N:7][C:6]=1[CH3:13])[CH3:2].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=2)O1>>[CH2:1]([O:3][C:4]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=2)=[N:7][C:6]=1[CH3:13])=[O:14])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1C
Reactant: CC1(C)OB(c2cncc(C(F)(F)F)c2)OC1(C)C
Product: CCOC(=O)c1c(C)cc(-c2cncc(C(F)(F)F)c2)nc1C

Procedure:
In analogy to the procedures described for example 1, for intermediate 5B and for intermediate 1, the title compound has been prepared by the following reaction sequence: i) 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester [Zhou, Y.; Bridger, G. J.; Skerlj, R. T.; Bogucki, D.; Yang, W.; Bourque, E.; Langille, J.; Li, T.-S.; Metz, M. U.S. Pat. Appl. Publ. (2005), US 2005277668 A1] was reacted with 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-pyridine (intermediate 6) to give 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid ethyl ester; ii) 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid ethyl ester has been saponified to give 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid; iii) 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless amorphous solid. MS: 433.3 (MH+).
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])/[CH:2]=[CH: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].C1C(C(OO)=[O:29])=CC=CC=1>C(Cl)(Cl)Cl>[O:29]1[CH: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])[CH:2]1[C:1]([O:20][CH3:21])=[O:19]
Reactant: O=C(OO)c1ccccc1
Reactant: CCCCCCCCCCCCCCC/C=C/C(=O)OC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC1OC1C(=O)OC

Procedure:
For preparation of racemic dihydrosphingosines, K. Sisido, et al., report in J. Org. Chem., Vol. 29, No. 9, pp. 2783-2784 (1964) a process comprising, for example, reacting methyl trans-2-octadecenoate with perbenzoic acid in chloroform to obtain methyl 2,3-epoxyoctadecanoate having formula (V'): ##STR3## whose planar structure is the same as that of the compound represented by formula (V) hereinafter described, hydrolyzing the ester (V'), cyclizing the resulting acid by reaction with benzylamine to obtain 2-benzylamino-3-hydroxyoctadecanoic acid (cyclization yield: 68%), converting the acid to a methyl ester, and reducing the ester in an ether solvent with lithium aluminum hydride (LiAlH4) (reduction yield: 71%). Reduction of such a carboxylic acid as 2-benzylamino-3-hydroxyoctadecanoic acid to an alcohol has generally been carried out by once esterifying the carboxylic acid and using LiAlH4 as a reducing agent as in the above report. However, LiAlH4 is a reagent unsuitable to industrial use because it is not only expensive but difficult to handle on account of reactivity with moisture in air.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:18])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH3:10])[N:6]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>COCCOC>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:9]([CH3:10])[C:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:25](=[O:28])[CH2:26][CH3:27])[S:3][CH:4]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CCC(=O)Cl
Reactant: CN(C(=O)Cc1csc(N)n1)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: COCCOC
Product: CCC(=O)Nc1nc(CC(=O)N(C)c2ccc(Cl)cc2)cs1
Yield: 52.2 %

Procedure:
A 300 ml reaction flask was charged with 6.0 g (0.021 mole) of 2-amino-4-[N-4-chlorophenyl-N-methyl(carbamoylmethyl)] thiazole, 100 ml of 1,2-dimethoxyethane and 2.6 g (0.03 mole) of pyridine. The propionyl chloride (2.8 g, 0.03 mole) which was dissolved in 15 ml of 1,2-dimethoxyethane was added portionwise and the reaction solution was heated at 65° for two hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic phase was extracted with water and dried over sodium sulfate. After evaporating most of the ethyl acetate, hexane was added. There was obtained 3.7 g (51%) of product, M.P. 153°-5°. N.M.R. (CDCl3) ∂1.2-1.4 (CH3), 2.3-2.5 (CH2), 3.3 (NCH3), 3.5 (0=CCH2), 6.5 (hetero-aromatic) 7.2-7.4 (aromatic).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8](C#N)[C:9]2[CH:10]=C[C:12]([F:17])=[C:13]([CH:16]=2)C#N)=[C:4]([CH2:20][CH3:21])[CH:3]=1.Cl.O.[CH3:24][C:25]([OH:27])=[O:26]>O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:16]=[CH:13][C:12]([F:17])=[C:24]([CH:10]=2)[C:25]([OH:27])=[O:26])=[C:4]([CH2:20][CH3:21])[CH:3]=1
Reactant: CC(=O)O
Reactant: CCc1cc(Cl)nnc1C(C#N)c1ccc(F)c(C#N)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc(Cl)nnc1Cc1ccc(F)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of Example 1, A2 (1 eq) in AcOH:conc.HCl:H2O (1:10:1, 0.065 M) was heated at reflux overnight. The reaction mixture was then cooled down to RT and diluted with water/EtOAc. The organic phase was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. MS (ES) C14H12ClFN2O2 required: 294/296. found: 295/297 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH:16]1[CH:21]=[C:20]2[C:22]([O:24][S:25](=[O:27])(=[O:26])[C:19]2=[CH:18][CH:17]=1)=[O:23].O>C(#N)C>[S:25]([C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][C:20]=1[C:22]([O:15][CH2:14][C:2]1([CH3:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13])=[O:23])([OH:27])(=[O:26])=[O:24]
Reactant: CC1(CO)CN(c2ccccc2)NC1=O
Reactant: O=C1OS(=O)(=O)c2ccccc21
Solvent: O
Solvent: CC#N
Product: CC1(COC(=O)c2ccccc2S(=O)(=O)O)CN(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 4-methyl-4-hydroxymethyl-1-phenyl-3-pyrazolidinone (Dimezone-S®) (10 g, 48.5 mmol) in neat acetonitrile (200 ml), there is added 2-sulfobenzoic acid cyclic anhydride (8.9 g, 48.5 mmol) all at the same time, at room temperature, while stirring. The reaction mixture is heated to reflux under nitrogen until complete dissolution is observed. The process is continued for 24 hours and the mixture is cooled in a bath of ice and water for 2 hours. A solid precipitant is obtained that is collected by filtration and washed with acetonitrile cooled by means of ice. After drying under vacuum, 17.9 g (95%) of 4-methyl-3-oxo-l-phenyl-pyrazolidin-4-yl)methyl 2-sulfobenzoate (Compound II) is isolated in the form of a whitish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([N+:19]([O-])=O)=[CH:17][C:6]2[N:7]([CH3:16])[C:8](=[O:15])[CH2:9][N:10]([CH2:12][C:13]#[N:14])[CH2:11][C:5]=2[CH:4]=1.O.NN.C(O)C>[Pd]>[NH2:19][C:18]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][C:13]#[N:14])[CH2:9][C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CN(CC#N)C2
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1N)N(C)C(=O)CN(CC#N)C2
Yield: 16.1 %

Procedure:
To a mixture of (7-Methoxy-1-methyl-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetonitrile (0.47 g, 0.0016 mol) and Hydrazine hydrate (2.00 mL, 0.0411 mol) in Ethanol (10 mL, 0.2 mol) was added 10% Pd/C (10:90, Palladium:carbon black, 0.047 g) and reacted in an analogous manner to example 712. The reaction was filtered and evaporated. This product was chromatographed on SiO2 (13 g) with (20-1) DCM/MeOH giving (8-Amino-7-methoxy-1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetonitrile as a tan solid (0.067 g, 16%). Mp 128-132° C.; LCMS (m/e)) 261 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.80 (s, 1H), 6.59 (s, 1H), 4.95 (s, 2H), 3.77 (s, 3H), 3.77-3.75 (d, 2H, J=9.35 Hz), 3.62 (s, 2H), 3.18 (s, 3H), 3.06 (s, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([C:13]([CH3:22])([CH3:21])[CH2:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:11][CH:12]=1.[Na].[I-].[CH3:25][S+](C)(C)=O>CS(C)=O>[CH3:21][C:13]([C:9]1[CH:8]=[C:7]([CH:2]2[O:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:12]=[CH:11][CH:10]=1)([CH3:22])[CH2:14][C:15]1([C:16]([F:18])([F:19])[F:17])[CH2:25][O:20]1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2OCCCO2)c1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na]
Solvent: CS(C)=O
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cccc(C2OCCCO2)c1
Reaction time: 2 h

Procedure:
To a solution of 4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one (1 g, 3 mmol) in 4.1 mL of anhydrous DMSO was added the sodium ylide of trimethylsulfoxonium iodide (3.0 mL of a 0.8M solution in DMSO) over 5 minutes. The reaction was stirred 2 hours and quenched with water and ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Removal of the volatiles in vacuo afforded 2-{3-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]phenyl}-[1,3]dioxane as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OCC)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][NH2:28].O>C(O)C>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([NH:27][NH2:28])=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A solution of 13B (750 mg, 2.134 mmol) in ethanol (5 mL) was treated with hydrazine.H2O (1.036 mL, 21.34 mmol), stirred at 80° C. for 2 h. No product was observed so more hydrazine.H2O (1.036 mL, 21.34 mmol) was added, and the solution was stirred at 150° C. in sealed tube overnight. Upon cooling, water was added and the resulting white solid was collected by filtration, washed with water and air dried to provide 14A (754 mg, >quantitative yield) as a white solid. MS (ES): m/z=338.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.16-7.40 (m, 10H); 6.58 (br. s, 1H); 3.76 (br. s, 2H); 3.55 (s, 4H); 2.42-2.51 (m, 1H); 1.79-1.97 (m, 5H); 1.25-1.42 (m, 4H).