Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24](O)=[O:25])=[CH:20]2)(=[O:13])=[O:12])(=[O:4])=[O:3].Cl.[C:28]([S:47][CH2:48][CH2:49][NH2:50])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]([NH:50][CH2:49][CH2:48][S:47][C:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:25])=[CH:20]2)(=[O:13])=[O:12])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a mixture of 7-{[2-(methylsulfonyl)phenylsulfonyl]amino}-1H-indole-2-carboxylic acid (1.00 g), 2-(tritylthio)ethylamine hydrochloride (0.92 g), 1H-1,2,3-benzotriazol-1-ol (0.41 g), triethylamine (0.42 mL) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.58 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.78 g, quantitative) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point 91-93° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:35])([F:34])[S:21](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:23])=[O:22].CCOC(C)=O>CN(C=O)C>[F:19][C:20]([F:35])([F:34])[S:21]([O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[O:10][CH3:11])(=[O:23])=[O:22]
Reactant: COc1cc(C=O)c(C)cc1O
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(C)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 4-Hydroxy-5-methoxy-2-methylbenzaldehyde (20.0 g, 122 mmol) in DMF (200 mL) at room temperature was added potassium carbonate (33.3 g, 241 mmol) and 4-nitrophenyl trifluoromethanesulfonate (49.0 g, 181 mmol) and the reaction mixture was stirred for 8 hr. EtOAc (600 mL) was added to the reaction mixture and the organic layer was washed three times with water, dried, filtered, and concentrated. The crude compound was then purified by flash chromatography (ethylacetate/hexanes 1:9→3:7) to provide 4-Formyl-2-methoxy-5-methylphenyl trifluoromethanesulfonate. 1H NMR (CDCl3, 500 MHz) δ 10.34 (s, 1H), 7.53 (s, 1H), 7.16 (s, 1H), 3.99 (s, 3H), 2.67 (s, 3H); LC/MS: (IE, m/z) [M+1]+=298.97; tR=3.44 min.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:17][C:18]1[C:19]([O:21][C:22](=[O:24])[CH:23]=1)=[O:20]>C(=S)=S>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:19](=[O:20])[C:18]([CH3:17])=[CH:23][C:22]([OH:24])=[O:21]
Reactant: O=C1CCCN1c1ccccc1
Reactant: CC1=CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=CC(=O)O)C(=O)c1ccccc1N1CCCC1=O
Reaction time: 40 h

Procedure:
66.7 g (0.5 mole) of anhydrous aluminum chloride are suspended in 150 ml of carbon disulphide. 32.2 g (0.2 mole) of N-phenyl-pyrrolidin-2-one and 22.4 g (0.2 mole) of methylmaleic anhydride are added, while stirring and cooling. The mixture is heated under reflux until a viscous mass is formed, and this is left to stand at room temperature for 40 hours, the solvent is decanted off and the mixture is decomposed carefully with icewater and concentrated aqueous hydrochloric acid and extracted with methylene cchloride or ethyl acetate. The organic phase is extracted with dilute sodium hydroxide solution, the aqueous phase is clarified by filtration, acidified with acetic acid and extracted and the extract is concentrated. The resulting oil is further reacted directly.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[C:41](O)(=[O:44])[CH2:42][CH3:43].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:41](=[O:44])[CH2:42][CH3:43])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: CCC(=O)O
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36, 0.05 g, 0.187 mmol) in dry DMF (1 mL) were added EDCI (0.039 g, 0.206 mmol), Hünig's base (0.060 g, 0.468 mmol) and propionic acid (0.021 g, 0.282 mmol) and the reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with EtOAc, poured into sat. NH4Cl solution (5 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.029 g, 48%) as a white solid. MS: 324.4 (M+H+).
Reaction SMILES: Cl.C[O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]=2[CH3:26])=[CH:9][CH:8]=1.[OH-:28].[Na+].[NH2:30]O.Cl>CO.O>[OH:28][NH:30][C:4](=[O:3])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]=2[CH3:26])=[CH:9][CH:8]=1
Reactant: NO
Reactant: [OH-]
Reactant: COC(=O)/C=C/c1ccc(CNCCc2c(C)[nH]c3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1[nH]c2ccccc2c1CCNCc1ccc(/C=C/C(=O)NO)cc1
Temperature: -15 °C
Reaction time: 7 h

Procedure:
(E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]phenyl)-acrylic acid methyl ester hydrochloride salt (90 g, 233.8 mmole) is placed in a 4-necked reaction flask and methanol (475 g) is added. The suspension is cooled to −15° C. A solution of sodium hydroxide (28.2 g, 705 mmole) in methanol (419.2 g) is added to the suspension at −15° C. (addition time ca. 30 minutes), followed by the addition of the hydroxylamine solution (100.3 g of a 50% solution in water, corresponding to 50.15 g hydroxylamine, 1518 mmole) at, this temperature (addition time ca. 30 minutes). Caution: it is important to use different addition funnels for the sodium hydroxide and hydroxylamine solutions respectively. Stirring is continued at −15° C. for an additional 7 hours until a conversion of >99.5 area % is achieved according to HPLC. The reaction mixture is warmed to 0° C., stirred for 5 hours at 0-5° C., warmed to 20° C. and stirring is continued for 8 hours at 20-25° C. De-mineralized water (225 g) is added to the suspension at 20-25° C. during 30 minutes to obtain a solution. The solution is filtered and the filter as well as the filter pipeline are washed with de-mineralized water (225 g). The pH of the solution is adjusted to 10.3-10.7 by the addition of an aqueous hydrochloric acid solution (ca. 140 g of a 7.8 m/m % solution in water). Seed crystals are added as a suspension of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base (80 mg) in water (5 g) and the mixture is stirred for ca. 30 minutes at 20-25° C., until a suspension is formed. The pH of the suspension is then adjusted to 8.5-9.0 by addition of an aqueous hydrochloric acid solution (ca. 108 g of a 7.8 m/m % solution in de-mineralized water) at 20-25° C. and stirring is continued for at least 30 minutes at 20-25° C. The solid product is isolated by filtration and the filter cake is washed with a 1:1 (v/v) mixture of demineralized water and methanol (140 mL). The wet product is dried at 45-50° C./5 mbar for 24 hours to obtain N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide. Yield: 81.15 g; 99.3% of the theory. HPLC analysis indicated 97.6 area % purity for the product, which comprised 3.2% w/w of water. The hydroxylamine content was found to be 345 ppm, which is sufficient for the preparation of the corresponding lactate salt with <5 ppm hydroxylamine.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:21])[CH2:17][C:18](=O)[CH3:19])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[NH3:24]>CO>[NH2:24]/[C:18](/[CH3:19])=[CH:17]\[C:16]([NH:15][C:5]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=1)=[O:21]
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Reactant: N
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-trifluoromethyl-4-morpholinophenyl)-3-oxobutanamide (4.0 g, 12.1 mmol), MeOH (20 mL) and ammonia (20 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@@H:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[NH:33][C:32](=[O:34])[N:31]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:30]=2[CH:41]=1>CCO.C(Cl)Cl>[C:17]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:20][C@@H:21]([OH:22])[CH2:23][N:38]3[CH2:37][CH2:36][CH:35]([N:31]4[C:30]5[CH:41]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=5[NH:33][C:32]4=[O:34])[CH2:40][CH2:39]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=3)[C:12]=2[CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2C[C@@H]2CO2)C1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCNCC1
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2C[C@@H](O)CN2CCC(n3c(=O)[nH]c4ccc(Cl)cc43)CC2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 11.7 %

Procedure:
(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (31 mg, 0.10 mmol) and 6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (36 mg, 0.17 mmol) were combined in EtOH (0.3 mL) and heated to 70° C. After 18 h the mixture was allowed to cool, diluted with CH2Cl2 and purified by preparative TLC (silica, 8% MeOH/CH2Cl2) to give 7 mg (12%) of the title compound. HPLC (reverse phase conditions), tR=3.49 min. MS (electrospray): m/z calculated for C30H3535Cl2N6O3 [M++H] 597.22. found 597.20. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 9.16 (br d, J=10.1 Hz, 1H), 7.55 (br m, 1H), 7.40-7.28 (m, 2H), 7.18 (br s, 1H), 7.03 and 6.98 (A and B of ABX (with fine splittings), Jab=8.4 Hz, 2H), 4.85 and 4.74 (A and B of ABX (with fine splittings), Jab=15.7 Hz, 1H), 4.62 (s, 1H), 4.29-4.18 (m, 4H), 4.09-4.00 (m, 2H), 3.91-3.71 (m, 2H), 3.16-2.78 (m, 4H), 2.55-2.50 (m, 4H), 2.43 (s, 1.5H), 2.41 (s, 1.5H), 2.23 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 1.84 (br s, 2H).
Reaction SMILES: C1(O)(O)CCCC1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O:28][C:29](=[O:31])[CH3:30])(=O)C>ClCCl>[C:29]([O:28][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OC1(O)CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 7 (10 g, 40 mmol, 1 equiv) and pyridine (22.6 mL, 280 mmol, 7 equiv) in dichloromethane (200 mL) was added p-toluenesulfonyl chloride (11.4 g, 60 mmol, 1.5 equiv). The mixture stirred at room temperature overnight. Pyridine (22.6 mL, 280 mmol, 7 equiv) and acetic anhydride (21.9 mL, 232 mmol, 5.8 equiv) were added at room temperature and the mixture was stirred overnight. The reaction was cooled to 5° C. and quenched with 2 N aq NaOH to pH 7. The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The resulting semi-solid was dissolved in isopropyl acetate (100 mL) and concentrated to dryness. This was repeated 2 more times. The resulting semi-solid was triturated in methyl tert-butyl ether (250 mL), filtered and dried under vacuum to afford 8.1 g of 8 (45%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][C:15]3([CH2:27][C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([NH:33][O:34]C5CCCCO5)=[O:32])[CH:24]=4)[O:19]3)[CH2:14][CH2:13]2)=[CH:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][C:15]3([CH2:27][C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([NH:33][OH:34])=[O:32])[CH:24]=4)[O:19]3)[CH2:14][CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CCCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(CN2CCCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NO)ccc2O3)c2ccccc21

Procedure:
(±)-(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (280 mg, 0.51 mmol) in DCM (5 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving after purification by preparative HPLC (±)-(E)-3-[1-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide (80 mg, trifluoroacetate salt) as a light brown solid.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][Br:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)n1ccc2cc(CBr)ccc21
Yield: 76.2 %

Procedure:
A suspension of the product of Step A (5.5 g 23.4 mmol) in 10 mL of CCl4 was heated to reflux. N-bromosuccinimide (4.6 g, 25.7 mmol) and several crystals (approximately 100 mg) of azoisobutyronitrile (AIBN) were added. The resultant solution was stirred at reflux for 4 hours. The solution was cooled, diluted with 1.5 L of CH2Cl2 and washed with 400 mL of H2O and 400 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated to a brown oil. The resultant oil was flash chromatographed eluting with 10:1 hexane/ethyl acetate to afford the titled compound (5.6g, 80%) as a yellow powder.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@@:11]2([CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[C@H:13]([CH3:14])[O:12]2)=[CH:7][CH:6]=1.C([S:24][C@H:25]1[CH2:30][O:29][C@@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH2:26]1)(=O)C>C(O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@:11]([OH:12])([C@H:13]([S:24][C@H:25]2[CH2:26][O:27][C@@H:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][CH2:30]2)[CH3:14])[CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:7][CH:6]=1
Reactant: CC(=O)S[C@H]1CO[C@@H](c2ccccc2)OC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](S[C@H]1CO[C@@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 72.2 %

Procedure:
1 ml (0.59 mmol) of a 4.8 M methanolic solution of sodium methoxide was added to a solution of 2.33 g (10 mmol) of (2R,3S)-2-(4-fluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane [prepared as described in Chem. Pharm. Bull., 43, 441-449 (1995)] and 2.38 g (10 mmol) of cis-5-(acetylthio)-2-phenyl-1,3-dioxane [prepared as descriptive in Step 6(i) above] in 40 ml of ethanol. The resulting mixture was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel (50 g) column using a 2:1 mixture of ethyl acetate and hexane as the eluant to afford 3.1 g (yield 72%) of the title compound as a brown foamy solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[CH3:28][C:25]([CH3:29])([CH2:24][CH2:23][CH2:22][CH2:21][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:26]#[N:27]
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Reactant: CC(C)(C#N)CCCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C#N)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure in Example 4 is followed but using 4,6-diphenyl-2-pyridinone (6.3 g)0 6-bromo-2,2-dimethylhexanonitrile (2.60 g) (prepared according to the method of M. Larcheveque et al., Bull. Soc. Chim. Fr., 1710 (1974)), silver carbonate (3.5 g) and toluene (300 cc). The product is purified by chromatography under pressure on silica gel (30-60 mm); eluent: n-hexane-ethyl acetate 9.5-0.5).yellowish solid. (m.p.=71° C.)
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=O)C.CO.[OH-].[Na+]>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]

Procedure:
1-Acetamido-2-nitro-4-phenoxybenzene is treated with 20 ml. methanol and 10 ml. 5 N aqueous sodium hydroxide at 20°-25° C for one hour. The mixture is diluted with water and the crude product filtered off. Recrystallization yields 1-amino-2-nitro-4-phenoxybenzene. This latter compound is treated in accordance with the first paragraph of Example VI to afford 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-phenoxybenzene.
Reaction SMILES: [C:1]([C:3]1[C:7](C)=[CH:6][S:5][C:4]=1[N:9]=[CH:10]OCC)#[N:2].[CH3:14][C:15]1[CH:24]=[C:23]([CH2:25][CH2:26][CH3:27])[CH:22]=[C:21]([CH3:28])[C:16]=1[O:17][CH2:18][CH2:19][NH2:20].[O-][CH2:30]C.[Na+]>C(O)C>[CH3:14][C:15]1[CH:24]=[C:23]([CH2:25][CH2:26][CH3:27])[CH:22]=[C:21]([CH3:28])[C:16]=1[O:17][CH2:18][CH2:19][NH:20][C:1]1[N:2]([CH3:30])[CH2:10][N:9]=[C:4]2[S:5][CH:6]=[CH:7][C:3]=12
Reactant: CCOC=Nc1scc(C)c1C#N
Reactant: CC[O-]
Reactant: CCCc1cc(C)c(OCCN)c(C)c1
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(C)c(OCCNC2=c3ccsc3=NCN2C)c(C)c1
Yield: 59 %

Procedure:
3.9 g (0.02 mole) of 3-cyano-2-ethoxymethyleneamino-4-methylthiophene and 4.1 g (0.02 mole) of 2-(2,6-dimethyl-4-propylphenoxy)ethylamine were dissolved in 30 ml of ethanol, and the solution was heated under reflux for 5 hours. It was then cooled and 50 ml of ethanol containing 0.05 mole of sodium ethoxide were added; the whole mixture was then heated under reflux for 6 hours. At the end of this time, the ethanol was distilled off and water was added to the residue. The oily phase was separated and extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulphate, after which the solvent was distilled off and the residue was subjected to column chromatography through silica gel eluted with a 9:1 by volume mixture of benzene and ethyl acetate, to give 4.2 g (yield 59%) of the desired Compound No. 16 in the form of colourless crystals melting at 86°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]1[N:13]=[C:14]([CH2:17][C:18]([CH3:20])=O)[S:15][CH:16]=1.[NH2:21]/[C:22](/[CH3:26])=[CH:23]\[C:24]#[N:25]>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]1[C:17]([C:14]2[S:15][CH:16]=[C:12]([CH3:11])[N:13]=2)=[C:18]([CH3:20])[NH:21][C:22]([CH3:26])=[C:23]1[C:24]#[N:25]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: C/C(N)=C/C#N
Reactant: CC(=O)Cc1nc(C)cs1
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2ccc(Cl)cc2Cl)C(c2nc(C)cs2)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.857 mmol) of 2,4-dichlorobenzaldehyde, 133 mg (0.857 mmol) of the compound from example 4A and 70 mg (0.857 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is taken up in 3 ml of ethyl acetate. The crystallizing solid is removed by filtration. The product obtained in this way is washed with a little diethyl ether. 85 mg (26% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][C:20]([F:26])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCO.[Pt]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:22]([NH2:23])=[CH:21][C:20]([F:26])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: [Pt]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(F)cnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
A mixture of 4-(benzyloxy)aniline (2.26 g), 2-chloro-5-fluoro-3-nitropyridine (2 g) and K2CO3 (3.13 g) in DMF (20 mL) was stirred at 120° C. for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The solid obtained above was dissolved in EtOH (20 mL), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]#N)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([OH:18])[CH3:17].S(=O)(=O)(O)[OH:20]>O>[CH2:16]([O:18][C:14](=[O:20])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1)[CH3:17]
Reactant: CCO
Reactant: O=S(=O)(O)O
Reactant: N#CCc1ccc(C2CCCCC2)cc1
Solvent: O
Product: CCOC(=O)Cc1ccc(C2CCCCC2)cc1

Procedure:
13.7 g of para-cyclohexyl-phenylacetonitrile, 21 ml of absolute ethanol, and 7.3 ml of concentrated sulfuric acid are boiled overnight. The mixture is then diluted with water and extracted several times with ethyl acetate. The solution is washed with sodium bicarbonate solution and water, and dried over sodium sulfate. The residue obtained on evaporation of the solvent is distilled in a high vacuum. There is obtained para-cyclohexylphenyl acetic acid ethyl ester boiling at 125°-127°C under a pressure of 0.5 mm of Hg.