Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.[N:47]1([CH2:54]CN2CCC(N)CC2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[N:47]1([CH2:54][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 5 analogously to the method described in example 1.
Reaction SMILES: [CH:1]([N:4]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:8]2[C:9](=[CH:10][CH:11]=[C:12]3[CH2:13][CH2:14][O:15][C:16]3=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1cccc2c1OCC2
Reactant: O=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)NC(c2ccccc2)c2ccc3c(c21)OCC3

Procedure:
A solution of 4.8 g. of 1-isopropyl-1-(2,3-dihydro-7-benzofuranyl)urea, 3.4 ml of benzaldehyde, 3 drops of methanesulfonic acid and 150 ml. of toluene is stirred and refluxed under a water separator for 18 hours. The cooled solution is washed with 150 ml. of water, dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an oil of 1-isopropyl-3,4,7,8-tetrahydro-4-phenyl-furo[3,2-h]quinazolin-2(1H)-one.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][CH:11]([C@H:14]2[CH2:16][C@H:15]2[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[OH:19][CH2:18][CH2:17][C@@H:15]1[CH2:16][C@@H:14]1[CH:11]1[CH2:10][CH2:9][N:8]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:13][CH2:12]1
Reactant: CC(C)OC(=O)Cl
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)OC(=O)N1CCC([C@H]2C[C@H]2CCO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Isopropyl chloroformate (0.12 μL, 1.0 mmol) was added dropwise to a solution of 2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (170 mg, 1.0 mmol) and cesium carbonate (650 mg, 2.0 mmol) in acetonitrile (5 mL). After total addition, the mixture was stirred for 2 hours at RT. The solution was concentrated under reduced pressure and the residue taken-up in 10 mL DCM. The solution was washed with water, the organics were collected, dried over sodium sulfate, filtered and the filtrate concentrated to dryness under reduced pressure. The residue by flash chromatography (20 g of silica gel, ISCO, eluted with a gradient 0-100% ethyl acetate in Hexane) to afford the title compound (189 mg, 74%). LC/MS 256 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O.O>[CH2:19]([O:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: O=Cc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.2 %

Procedure:
4-Bromosalicylaldehyde (4.02 g, 20.0 mmol) [prepared from 3-bromophenyl analogous to the procedure of Casiraghi, et. al. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1978), 318-21] was dissolved in anhydrous N,N-dimethylformamide (13 mL). Potassium carbonate (3.9 g, 28.0 mmol) was added as a solid to give a yellow suspension. Allyl bromide (2.6 mL, 3.63 g, 30.0 mmol) was added via syringe. The reaction stirred for 17 h at room temperature and was then diluted with water and extracted three times with 1:1 ethyl acetate-hexane. The combined organic layers were washed with water (5×), brine, dried over sodium sulfate, filtered and concentrated to afford 2-(allyloxy)-4-bromobenzaldehyde (4.83 g, 100% yield) as a yellow solid which was used without further purification in the next step; Rf 0.38 (1:9 ethyl acetate-hexane); MS [M+H]+241.0.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C@H:7]([C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=O)[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.B#B.Cl>C1COCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C@H:7]([CH2:16][NH:18][CH:19]([CH3:20])[CH3:21])[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)NC(=O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Agent: B#B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)NC[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Yield: 208.9 %

Procedure:
A solution of cis-6-chloro-4-phenyl-N-(2-propyl)-1,3-benzodioxan-2-carboxamide (6.6 g, 20.0 mmoles) in 400 ml of anhydrous THF was treated with 80 ml (80 mmoles) of diborane in THF solution (1M as BH3) and the reaction mixture was worked up essentially as described in Example 5b. The oily amine was converted to the hydrochloride in anhydrous ether; 7.4 g of colorless powder was obtained. Recrystallization from absolute EtOH gave 5.96 g (84%) of colorless crystals; mp 224.5°-225.5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([OH:25])=[O:24].[CH3:26]S(C)=O.CI.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24]
Reactant: Cc1c(-c2ccc(C(F)(F)F)cc2)nc2ccc(Br)cc2c1C(=O)O
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: COC(=O)c1c(C)c(-c2ccc(C(F)(F)F)cc2)nc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
6-Bromo-3-methyl-2-[4-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (15.6 g, 38.0 mmol), dimethyl sulfoxide (DMSO) (190 ml), methyl iodide (4.76 mL, 76 mmol) and cesium carbonate (12.39 g, 38.0 mmol) were added to a 500 mL flask The mixture was stirred at RT for 2 h. Water (200 mL) was added to the resulting slurry, and the mixture was stirred for 10 min, the solid was collected by filtration, and the filter cake was washed with 500 mL of water. The resulting solid was dried under reduced pressure to afford the desired product as a tan solid (15.75 g, 98%). MS (m/z) 426.0 (M+H+).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1>Cl>[O:5]1[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=[C:4]1[CH:3]=[O:2]
Reactant: COC(OC)c1cc(=O)c2ccccc2o1
Agent: Cl
Product: O=Cc1cc(=O)c2ccccc2o1
Yield: 81.6 %

Procedure:
A stirred solution of 2-(dimethoxymethyl)-4H-1-benzopyran-4-one (1.1 g, 0.005 m) in 5 N hydrochloric acid (20 ml) was heated at 100° for 3 hours. The reaction mixture was cooled and extracted with CHCl3. The extracts were dried over MgSO4 and evaporated under reduced pressure to give a crystalline product. Recrystallization from ethyl acetate gave off-white crystals (710 mg, 81%), m.p. 159°-161°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[O:25][CH:26]([CH2:29][F:30])[CH2:27][F:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([NH:16][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:18]([O:25][CH:26]([CH2:27][F:28])[CH2:29][F:30])[CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(N)c(OC(CF)CF)c1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(C#N)cc3OC(CF)CF)c2c1C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.2 g), 4-amino-3-(2-fluoro-1-fluoromethyl-ethoxy)-benzonitrile (0.17 g), p-toluenesulfonic acid monohydrate (0.16 g) and isopropanol (3.0 ml) were stirred at 90° C. for 2 hours. Then the mixture was poured in water and filtrated. The solid was washed with water and dried in an oven at 70° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Fc1ccc(C2=CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccc(F)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (100 g), triethylamine (50 cc) and 4-(4-fluorophenyl) 1,2,3,6-tetrahydropyridine (77.9 in toluene (950 cc). The mixture is heated for 7 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, 2-{3-[4-(4-fluorophenyl)-1,2,3,6-tetrahydro-l-pyridyl]propyl}-naphtho[1,8-cd]isothiazole 1,1-dioxide (105.4 g) is obtained in the form of a brown oil [Rf=0.8; thin-layer chromatography on silica gel; eluant: ethyl acetate]. This oil is converted to the hydrochloride, m.p. 224° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)=[O:2].[C:23](=O)=O.CC(C)=O.C[Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH3:23]
Reactant: O=C=O
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Agent: C[Mg]Br
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(C)cc(C(C)O)c2OC1C(F)(F)F
Reaction time: 2 h
Yield: 54 %

Procedure:
The ethyl 8-formyl-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605a, Step 1 (1.00 g, 3.18 mmole) was dissolved in anhydrous THF (10 mL) and the solution was cooled to −78° C. (dry ice/acetone). Methylmagnesium bromide (1.16 mL, 3.50 mmole) was added dropwise to the above solution, which was allowed to stir for 2 hours. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by flash chromatography (silica gel) with 10% MeOH/ CH2Cl2 to give a light yellow oil (0.3g, 54%): GCMS m/z 330.0 (M+). 1H NMR (CDCl3/400 MHz) 7.67 (s, 1H), 7.26 (s, 1H), 6.94 (s, 1H), 5.68 (q, 1H, J=7.0 Hz), 5.11 (m, 1H), 4.30 (m, 2H), 2.28 (s, 3H), 1.47 (m, 3H), 1.34 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[C:14]([O:20][CH3:21])[CH:13]=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=2[O:20][CH3:21])[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(F)ccc1[Mg]Br
Reactant: O=Cc1cccc(Br)c1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(F)ccc1C(O)c1cccc(Br)c1F
Reaction time: 0.83 h
Yield: 82 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (1.5 g, 7.39 mmol) in THF (Volume: 32.1 ml) cooled to 0° C. was added (4-fluoro-2-methoxyphenyl) magnesium bromide (17.73 ml, 8.87 mmol). After 50 min, additional (4-fluoro-2-methoxyphenyl)magnesium bromide (17.73 ml, 8.87 mmol) was added. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-30% EtOAc in hexanes over 30 min, tr=17 min) gave the title compound (2.10 g, 6.06 mmol, 82% yield) as a colorless liquid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>O>[C:22]([O:15][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:8])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Oc1ccccc1C(=O)c1ccccc1

Procedure:
1 g. (0.005 mole) of O-hydroxybenzophenone was warmed in 25 mls of dry pyridine containing 1 g (0.01 mole) of pivaloyl chloride for 3 hrs. at 50° C. Poured into H2O containing 2 g of Na2CO3 and extracted with EtOAc+Et2O and washed with H2O. After drying over Na2SO4 and filtration, the product was isolated by evaporation of the solvent. Oily material. 1.2 g. (85%) yield.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: COC(CN)OC
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NCC(OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
214 g (2 mol) of ethyl chloroformate are added dropwise to 214 g (2 mol) of aminoacetaldehyde dimethyl acetal in 1 l of toluene and 90 g of NaOH in 500 ml of water at 10° C. The mixture is stirred at room temperature for a further 2 hours and the aqueous phase is separated off, saturated with sodium chloride and extracted with toluene. The toluene solutions are dried over magnesium sulphate and concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CNC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 4-methoxybenzenesulfonyl chloride (25 g) in tetrahydrofuran (25 ml) was added dimethylamine (50% solution in water, 25 ml). After addition was complete, the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated to give 4-methoxy-N,N-dimethylbenzenesulfonamide (38 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH3:14]>C(O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCO
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
131 g of product of Example 3 are added portionwise to 1 l of ethanol saturated with ammonia. The reaction mixture is stirred at ambient temperature for 24 h, then concentrated and water is added thereto. The solid obtained is filtered, then washed with isopropanol and pentane.
Reaction SMILES: [OH-].[K+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=O)/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].[NH2:15][NH2:16]>CO>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH2:9][CH:10]([C:11]([OH:13])=[O:12])[NH:16][N:15]=1
Reactant: O=C(O)/C=C/C(=O)c1cccs1
Reactant: NN
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC(c2cccs2)=NN1
Yield: 82.6 %

Procedure:
Potassium hydroxide (3.3 g) is dissolved in 100 cc of methanol and 9.1 g of 4-(2-thienyl)-4-oxocrotonic acid is added. To the resulting solution is added 2 g of hydrazine and the solution is refluxed for 2 hours. The methanol is removed and the viscous residue dissolved in 80 cc of water. The solution is made strongly acid with 20% HCl and a precipitate forms. It is filtered and air-dried to yield 8.1 g of the title compound, melting point 163°-165° C., dec. After recrystallization from ethanol the compound is constant melting at 171°-173° C., dec.
Reaction SMILES: [CH:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[Na+].O1CCOCC1>[CH:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1=NOC(C2CCCCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1=NOC(C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-cyclohexyl-4,5-dihydroisoxazole-3-carboxylate (0.1 g; 0.44 mmol) was dissolved in a mixture of sodium hydroxide (5 mL, 1M in water) and dioxane (2 mL). The reaction mixture was stirred vigorously at room temperature overnight and concentrated under reduced pressure. The resulting solution was acidified and extracted with ethyl acetate, dried and concentrated under reduced pressure, the crude material was used without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C1C=CC=CC=1>[C:22]1([O:21][C:19]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)C(C#N)=NO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=NOC(=O)Oc1ccccc1
Temperature: 0 °C
Yield: 124.8 %

Procedure:
In dry benzene (50 ml), ethyl 2-hydroxyimino-2-cyanoacetate (7.1 g) and triethylamine (7.0 ml) are dissolved, and the obtained solution is cooled with ice-water. A solution of phenyl chloroformate (7.8 g) in dry benzene (50 ml) is dropwise added thereto while stirring, and the resulting mixture is stirred for 1 hour and allowed to stand over night. The reaction mixture is filtered, and the filtrate is washed with water, dried and concentrated to give ethyl 2-phenyloxycarbonyloxyimino-2-cyanoacetate (16.3 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S@@:20]([NH2:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[N:22][S@@:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: CC(C)(C=O)c1ccc(Cl)cc1
Reactant: Cc1ccc([S@@](N)=O)cc1
Solvent: ClCCl
Product: Cc1ccc([S@@](=O)N=CC(C)(C)c2ccc(Cl)cc2)cc1

Procedure:
The 2-(4-chlorophenyl)-2-methylpropionaldehyde (5.60 g, 30.7 mmol) and (S)-4-methyl-benzenesulfinic acid amide (5.00 g, 32.2 mmol) were dissolved in 300 mL of DCM and treated with Ti(OEt)4 (32.1 mL, 153 mmol). The mixture was heated to reflux under nitrogen for four hours. The solution was cooled in an ice bath and quenched with the dropwise-addition of 200 mL of water. The resulting precipitate (Ti salts) were removed by filtration through a plug of celite and washed with DCM. The resulting filtrate was separated, and the aqueous was extracted with more DCM. The combined organic was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by filtration through a plug of silica gel (hexanes:ethyl acetate, 1:1) to afford the (R)-4-methylbenzenesulfinic acid [2-(4-chlorophenyl)-2-methylpropyliden]-amide as a colorless oil, which solidified upon standing to give a white solid (9.28 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.14 (m, 2H), 2.42 (s, 3H), 1.52 (s, 3H), 1.47 (s, 3H).
Reaction SMILES: C(C1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:22])[N:4]=1)#N.O.[C:24]([OH:27])(=[O:26])[CH3:25]>Cl.C(Cl)(Cl)Cl.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:22])[N:4]=[C:25]([C:24]([OH:27])=[O:26])[CH:8]=1
Reactant: CC(=O)O
Reactant: COc1cc(C#N)nc(Oc2c(Cl)cccc2C(F)(F)F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(Oc2c(Cl)cccc2C(F)(F)F)nc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-cyano-4-methoxy-6-[2-chloro-6-(trifluoromethyl) phenoxy] pyridine (2.88 g, 0.0088 mol) was suspended in about 20 ml of concentrated hydrochloric acid and about 10 ml of acetic acid. The obtained suspension was stirred at about 100° C. for about 4 hours. After being allowed to stand for cooling, the obtained reaction solution was mixed with water, and then distributed in chloroform-water. The obtained solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated, thereby obtaining an aimed product.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]1[CH2:9][CH2:8][CH:7]([CH:10]=[CH:11][CH:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]>C(OCC)C>[OH:4][CH:5]1[CH2:9][CH2:8][CH:7]([CH:10]=[CH:11][CH:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:3])=[O:26]
Reactant: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)OC
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of diazomethane (0.327 g.) in dry diethyl ether (10 ml.) was added to a solution of 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoic acid (0.4 g.) [prepared as described in Example 1] in dry diethyl ether (10 ml.). The resulting solution was allowed to stand at ambient temperature for 18 hours, during which time a solid precipitated. The solid was removed by filtration and the filtrate evaporated. The remaining traces of ether were removed from the residue by pumping under high vacuum to give methyl 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoate (0.3 g., 72%). (Found: C, 70.8; H, 10.6. C21H38O4 requires C, 71.25; H, 10.72%) νmax 1730 cm-1, 980 cm-1 (liquid film). N.M.R. (approximately 10% solution in deuterochloroform) 0.92δ (triplet J=5c/s, terminal CH3) 1.7, 1.4δ (overlapping multiplets, cyclic and chain CH2), 2.38δ (triplet J=6.5c/s, CH2C=0), 2.70δ (broad singlet, --OH), 3.76δ (singlet --COOCH3), 4.32, 4.15 and 4.00δ (overlapping multiplets, cis and trans ##EQU7## 5.62δ (multiplet, ##EQU8##
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccccc2)n1Cc1ccccc1

Procedure:
The reaction procedure of Example 11 was followed except that 150 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 6 mg of lithium hydride and 0.070 ml of benzyl bromide were used. As a result, 130 mg of 3-benzyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.