Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].C(N(C(C)C)CC)(C)C.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH2:11][OH:12])[CH2:25][CH2:24]1
Reactant: CN1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCN(c2ccc([N+](=O)[O-])cc2CO)CC1

Procedure:
A mixture of (2-fluoro-5-nitrophenyl)methanol (4.500 g, 26.3 mmol), diisopropylethylamine (6.89 mL, 39.4 mmol), and 1-methyl-1,4-diazepane (4.25 mL, 34.2 mmol) in acetonitrile (150 mL) was refluxed for 24 hours. The solvent was evaporated. The residue was treated with saturated aqueous NaHCO3 and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4 and filtered. The title compound was crystallized from the organic layers.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:11].[N:12](OC)=[O:13]>>[OH:13][N:12]=[C:8]([C:9]#[N:10])[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: Cc1ccc(CC#N)cc1C
Reactant: CON=O
Product: Cc1ccc(C(C#N)=NO)cc1C
Yield: 51.2 %

Procedure:
In a sulfonation flask, 37.6 g (0.26 mol) of 3,4-dimethylacetonitrile are reacted with 0.52 mol of gaseous methyl nitrite, as described under 3.1. After the customary isolation, 23.2 g (50%) of α-hydroxyimino-3,4-dimethylbenzylcyanide are obtained as a brown resin. This crude product is used in the next step without any further purification. The 1H-NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][CH:19]2[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:27])[C@:7]1([CH3:26])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:25])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[CH2:28]([SH:30])[CH3:29].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:30][CH2:28][CH3:29])[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:27])[C@:7]1([CH3:26])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:25])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CCS
Reactant: CSC1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Reaction time: 1 h

Procedure:
To a solution of 11β-acetyloxy-9-fluoro-17-(methylthio)androsta-1,4-diene-3-one (632 mg) in dry dichloromethane (20 ml) containing dry ethanethiol (0.6 ml) is added boron trifluoride etherate (0.25 ml). After one hour, the mixture is added to a NaHCO3 solution and extracted with chloroform. The chloroform solution is washed with water, dried (MgSO4 anhydrous), and evaporated to afford the title compound (620 mg) contaminated with a small amount of 11β-acetyloxy-9-fluoroandrosta-1,4-diene-3,17-dione. This material is used in the next step without further purification. A specimen crystallized from acetone-hexane shows melting point 140°-142° C. and a consistent nmr spectrum.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][NH:13][NH2:14]>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:10])[N:13]([CH3:12])[NH2:14])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(I)ccc1N=C=S
Reactant: CNN
Solvent: CCO
Product: Cc1cc(I)ccc1NC(=S)N(C)N
Yield: 64.2 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 22.3 g (0.0810 mole) of 4-iodo-2-methylphenyl isothiocyanate with 3.74 g (0.0811 mole) of methylhydrazine in 175 ml of ethanol yielded 16.7 g of 4-(4-iodo-2-methylphenyl)-2-methyl-3-thiosemicarbazide as a solid, mp 160°-161° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=[O:10].C(N(CC)CC)C.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:18]1([NH:24][C:25]([N:1]2[CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]2=[O:10])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C1CCC(=O)N1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(=O)N1C(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 66.8 %

Procedure:
In this example, 14.3 g of methyl 2-pyrolidone-5-carboxylate and 10.1 g triethylamine are dissolved in 100 ml of ethyl acetate. Phenyl isocyanate (11.9 g) is added thereto, and the resulting solution is left standing at room temperature overnight. The reaction mixture is then filtered, and the filtrate is washed twice with 100 ml of 1N hydrochloric acid, and then three times with 100 ml water. Then, the filtrate is dried over anhydrous sodium sulfate, and then filtered. The filtrate is concentrated under reduced pressure, and the resulting viscous material is dissolved in 100 ml ether, admixed with 100 ml n-hexane, and recrystallized, whereby methyl 1-phenylcarbamoyl-2-pyrolidone-5-carboxylate (compound number 4; 17.5 g; mp 91°-92° C.) is obtained. Yield: 66.8%.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[C:5]=2[N:6]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[C:5]=2[N:6]=1
Reactant: CCOC(=O)C1CCc2sc(Br)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCc2sc(Br)nc21
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of the product from step A (4.92 g, 17.82 mmol) was dissolved in methanol (20 mL) and added dropwise to a mixture of 5 N NaOH (4.25 mL, 21.25 mmol), water (16 mL) and methanol (30 mL). After addition was complete the mixture was stirred for 2 h. The methanol was removed by evaporation and the pH of the remaining aqueous was adjusted to ˜2.5 with conc. HCl. The mixture was saturated with solid NaCl and extracted with EtOAc (×3); combined EtOAc layers washed with sat. NaCl, dried over Na2SO4 and treated with activated charcoal overnight. The filtered mixture was evaporated. The residue was triturated with EtOAc, and the solid filtered to give 1.94 g of the desired product. The mother liquors were evaporated and purified by MPLC using a gradient rising from 100% Hexanes to 100% EtOAc in Hexanes to give a further 0.82 g of the title product (2.76 g in total, 62%) as an off white solid. 1H NMR (500 MHz CDCl3) δ: 4.04 (m, 1H), 3.02-3.08 (m, 1H), 2.88-2.94 (m, 1H), 2.78-2.83 (m, 2H).
Reaction SMILES: [CH:1]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:22]=[O:23].S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[C:15]1([CH3:21])[C:16]([CH:22]=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccccc1
Reactant: C=O
Agent: CCC(C)c1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccccc1C=O

Procedure:
To a mixture of 19.4 parts of 5-sec-butylsalicylic acid, 18.4 parts of toluene, 3.8 parts of 87% paraformaldehyde and 30 parts of acetic acid was added 2.0 parts of 95% sulfuric acid (catalyst). After being heated under reflux for 4 hours, the reaction mixture was washed with water, and unreacted toluene and water were removed by vacuum distillation to give 31 parts of 5-sec-butylsalicylic acid-toluene-formaldehyde co-condensation product. 10 parts of the co-condensation product was added to 14 parts of aqueous 10% sodium hydroxide solution and dissolved at 80° C. The resulting solution was cooled to 40° C., and 2.4 parts of zinc chloride was added thereto. After the reaction had been allowed to proceed at 40° C. for 1 hour, precipitates formed were collected by filtration, washed with water and dried to give 11.5 parts of zinc salt of 5-sec-butylsalicylic acid-toluene-formaldehyde co-condensation product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>ClCCl>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:31](=[O:34])[CH2:32][CH3:33])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCC(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC
Reaction time: 15 h

Procedure:
To a solution of 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol), triethylamine (0.20 ml, 14.50 mmol) in dichloromethane (8.0 ml), propionyl chloride (134 mg, 1.45 mmol) was added at room temperature. The mixture was stirred for 15 hours. The solvent was removed under diminished pressure. After evaporation, the mixture was stirred in acetonitrile/methanol (1:2, 9.0 ml) with aqueous ammonia (3.0 ml) for 3 hours. Water (50 ml) was added and the mixture was extracted three times with ethyl acetate (3×50 ml). The combined organic layers were washed with aqueous hydrochloric acid (1N), brine, dried and evaporated to afford a residue purified by HPLC. The title compound was obtained as white powder (19 mg).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([OH:31])[CH:25]=[CH:26][CH:27]=2)[N:22]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH3:54][CH:55]([CH3:62])[CH2:56][CH2:57][CH:58](O)[CH2:59][CH3:60]>>[CH2:59]([CH:58]([O:31][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[N:22]=[C:21]([NH2:20])[CH:30]=[CH:29]2)[CH2:57][CH2:56][CH:55]([CH3:62])[CH3:54])[CH3:60]
Reactant: CCC(O)CCC(C)C
Reactant: Nc1ccc2cccc(O)c2n1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC(CCC(C)C)Oc1cccc2ccc(N)nc12
Reaction time: 0.17 h

Procedure:
A 7.5 mL conical microwave vessel (Personal Chemistry) equipped with a septum cap and a magnetic stirring bar was charged with PS-PPh3 resin (Aldrich Chemical Co., Inc, 140 mg, 4.40 equiv), 2-amino-8-hydroxyquinoline (15.0 mg, 0.0960 mmol) and DBAD (69 mg, 3.2 equiv) and purged by passing a stream of N2 for 45 seconds. Anhydr. THF (1.5 mL) was added and contents of the vessel were stirred for 10 min. Then, neat 6-methyl-3-heptanol (4 equiv) was added to the vessel and the resulting suspension was irradiated in Personal Chemistry Smith Synthesizer (150° C. for 330 s; 300 W). The suspension was then filtered, and the resin washed with THF (3×3.0 mL). The filtrate and washings were combined and evaporated in vacuo. The residue was then treated with 6.0 mL of 4 M HCl in dioxane at room temperature for 4 h. The resulting solution was evaporated in vacuo. The residue was dissolved in 1.5 mL of a 1:1 mixture of DMSO/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (500 MHz, CDCl3) δ ppm 7.96 (d, 1H), 7.29 (t, 1H), 7.19 (m, 1H), 7.10 (d, 1H), 7.05 (br d, 1H), 4.37 (m, 1H), 1.91 (m, 2H), 1.78 (m, 2H), 1.55 (m, 1H), 1.35 (m, 1H), 1.24 (m, 1H), 0.98 (t, 3H), 0.87 (m, 6H); MS (DCI/NH3) m/z 273 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=1>CC#N>[CH2:5]([O:4][C:2]([C:11]1[N:12]([CH3:13])[C:8]([Br:7])=[CH:9][N:10]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cn1cncc1Br
Solvent: CC#N
Product: CCOC(=O)c1ncc(Br)n1C
Temperature: 25 °C
Yield: 55.3 %

Procedure:
Ethyl chloroformate (1.19 mL, 12.4 mmol) in MeCN (5 mL) was added dropwise to a 1.00 g (6.21 mmol) of 5-bromo-1-methyl-1H-imidazole (Aldrich) in 30 mL of MeCN under N2. The mixture was stirred and allowed to warm to rt overnight. The mixture was concentrated and the residue was treated with 2M NaOH (100 mL) and extratcted with CH2Cl2 (3×100 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, concentrated, and chromatographed (0-50% EtOAc in hexanes) to give the 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester as a yellow oil (800 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:5][N:6]=1.[C:14](OCC)(=[O:19])[CH2:15][C:16]([CH3:18])=O>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:16]([CH3:18])=[CH:15][C:14](=[O:19])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCSc1nnc(N)s1
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Product: CCCCCCSc1nn2c(=O)cc(C)nc2s1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Seven (7.0) grams of the thus obtained 2-amino-5-hexylthio-1,3,4-thiadiazole and 4.3 g of ethyl acetoacetate were mixed with 8 g of polyphosphoric acid, and the mixture was heated to 130°-150° C. and stirred for 30 minutes. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively, dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by developing on a silica gel column, and eluting with an ethylacetate/n-hexane (1:1) mixture, and thus 7.5 g of 2-hexylthio-7-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Refraction index nD20 : 1.6003. Yield 82%.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CO.[NH4+:12]>>[NH2:12][CH2:3][C@H:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[OH:1]
Reactant: c1cncc([C@H]2CO2)c1
Reactant: [NH4+]
Solvent: CO
Product: NC[C@@H](O)c1cccnc1

Procedure:
The title compound was prepared from 3-[(2S)-oxiranyl]pyridine (which was obtained in Example 129) and saturated ammonium methanol in substantially the same manner, as described in Example 124. The product was obtained as a brown oil; 1H NMR (400 MHz, DMSO-d6) δ 1.60 (brs, 2 H), 2.59–2.71 (m, 2 H), 4.47–4.50 (m, 1 H), 5.20 (brs, 1 H), 7.31–7.34 (m, 1 H), 7.68–7.71 (m, 1 H), 8.42–8.43 (m, 1 H), 8.50–8.51 (m, 1 H); MS (ES) m/z: 139 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1.O>[CH:41]1([S:47]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:49])=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)C2CCCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (664 mg) was added dropwise, and the mixture was stirred for 5 min. Cyclohexanesulfonyl chloride (367 mg) was added and the mixture was further stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 420 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC([C:25]2([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)CCC[N:27]([CH2:31]C(O)=O)[C:26]2=O)=CC=1.FC1C=C2C(CCNC2)=CC=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:42][C:39]1[CH:38]=[C:37]2[C:36]([CH2:25][CH2:26][N:27]([C:14](=[O:16])[CH2:13][N:10]3[CH2:11][CH2:12][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:17])[CH2:31]2)=[CH:41][CH:40]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: Fc1ccc2c(c1)CNCC2
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1CCc2ccc(F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 216A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 7-fluoro-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.20 (m, 2H), 7.16-6.96 (m, 3H), 6.95-6.75 (m, 2H), 4.66 (d, J=26.3, 2H), 4.34 (d, J=16.0, 1H), 4.22-4.03 (m, 1H), 3.83 (dd, J=5.7, 11.4, 1H), 3.75-3.49 (m, 4H), 2.87 (dd, J=5.8, 11.7, 2H), 2.68-2.45 (m, 1H), 2.16 (dd, J=7.7, 13.2, 1H)); MS (DCI) m/z 371.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.[Na+].[I-:15]>O1CCOCC1.[Cu]I>[I:15][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)c1ccc(Br)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC(C)c1ccc(I)cc1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To 8.70 g (35.9 mmol) N-(1-(4-bromophenyl)ethyl)acetamide (III.2) in 100 mL 1,4-dioxane are added 0.69 g (3.62 mmol) CuI, 0.97 mL (9.11 mmol) N,N″-dimethyl-ethylendiamine and 10.8 g (71.9 mmol) NaI. The reaction mixture is stirred at 120° C. for 3 d. The mixture is allowed to cool to r.t. and half of the solvent is removed in vacuo. EtOAc and diluted aq. ammonia solution are added and the layers are separated. The aq. layer is once more extracted with EtOAc. The organic layers are combined, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is triturated with diethylether and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:21][CH3:22])[CH2:30][CH2:31]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Reactant: CCc1ccccc1N1CCNCC1
Product: CCc1ccccc1N1CCN(C(=S)Nc2nc(C)c(C)nc2OC)CC1
Yield: 64 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH3:31][CH:32]([CH3:36])[CH2:33][CH2:34]I>>[CH3:31][CH:32]([CH3:36])[CH2:33][CH2:34][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CC(C)CCI
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 3 g (7.9 mmol) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate, 0.54 g (13.5 mmol) of NaH in 60% of mineral oil and 1.67 g (11.08 mmol) of 3-methylbutyl iodide. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 2.7 g (77% of yield) of the desired product. Melting point=150-151° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14]O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[CH:1]1[C:13]2[CH:12]([CH2:14][Cl:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1c2ccccc2-c2ccccc21
Product: ClCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 70 %

Procedure:
The precursor for Fm—S—Ph—CO2H, 9-fluorenylmethyl chloide (Fm—Cl) was synthesized as follows. A solution of 25.0 g of 9-fluorenmethanol (127 mmol, ALDRICH® Chemical Company was refluxed with 150 ml of thionyl chloride. for 30 minutes. The excess thionyl chloride was a removed by distillation and the residue distilled at reduced pressure, then crystallized from ethanol two times to afford 19.2 g of 9-fluorenylmethyl chloride (89.4 mmol, 70%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:26][CH:11]3[CH2:12][C:13]([CH3:15])([CH3:14])[N:8]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:9]([CH3:18])([CH3:17])[CH2:10]3)[CH2:12][C:13]2([CH3:15])[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reactant: NCCCCCCN
Product: CC1(C)CC(NCCCCCCNC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1

Procedure:
The product is prepared as described in Example II-1, by reaction of 126.7 g (0.5 moles) of 1-cyclohexyloxy-2,2,6,6-tetramethyl-4-oxopiperidine and 30.2 g (0.26 moles) of 1,6-hexanediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:22][CH2:23][C:24](N)=[O:25])[CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[OH:28]>[OH-].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:22][CH2:23][C:24]([OH:25])=[O:28])[CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: NC(=O)COc1ccc2c(c1)CCCC2NS(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)COc1ccc2c(c1)CCCC2NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
10 mmol of 5-(4-chlorobenzenesulphonylamino)-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetamide are heated under reflux in 12 ml of 2N KOH and 40 ml of MeOH for 6 hours. The methanol is stripped off, 30 ml of 1N KOH are added and the mixture is extracted by shaking twice with CH2Cl2. The H2O phase is brough to pH 2 with concentrated HCl and the precipitates is filtered off and dried thoroughly.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:7])[CH2:5][SH:6].[CH3:8][O:9][C:10](=[O:14])[C:11]([Cl:13])=[CH2:12]>O>[CH3:8][O:9][C:10](=[O:14])[CH:11]([Cl:13])[CH2:12][S:6][CH2:5][C:4]([O:3][CH3:2])=[O:7]
Reactant: C=C(Cl)C(=O)OC
Reactant: COC(=O)CS
Agent: [Na]
Solvent: O
Product: COC(=O)CSCC(Cl)C(=O)OC
Yield: 99.6 %

Procedure:
0.076 gram (3.31 mmoles) of metallic sodium were dissolved in 17.97 grams (169 mmoles) of thioglycolic acid methyl ester. This solution was then subsequently under stirring dropped into 20.0 grams (166 mmoles) of freshly distilled 2-chloro-acrylic acid methyl ester dissolved in 30 ml of water free methylene chloride within 1 hour at 25° C. After 4 hours post reaction at 25° C. it was worked up according to Example 1. There were obtained 37.5 grams (99.6% of theory) of 2-chloro-3-methoxycarbonylmethylmercapto-propionic acid methyl ester as a yellowish oil.