Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:19][NH:20][C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][CH2:42]Br)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O.O1CCCC1>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]([CH2:42][CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:38])[N:20]=[C:11]3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCOC(=O)c1n[nH]c2c1CCc1cnc(Nc3ccccc3)nc1-2
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c(nn1CCCNC(=O)OC(C)(C)C)-c1nc(Nc3ccccc3)ncc1CC2

Procedure:
500 mg of ethyl 8-anilino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.5 mmol) were dissolved in 10 mL of dry dimethylformamide and 1.63 mL of 1 M lithium tert-butoxide in tetrahydrofuran were added to the cooled solution. After 30 minutes under stirring at 0° C. a solution of 432 mg of tert-butoxycarbonylaminopropyl bromide in 8 mL of dry tetrahydrofuran were added dropwise. After a night at room temperature the mixture was poured into a solution of NaH2PO4 and extracted with dichloromethane. The organic layer was then dried over Na2SO4 and the solvent evaporated, giving an oil that was treated according to the following step 7, without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C([Mg]Cl)(C)C.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]C(Cl)=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=1)[CH3:2]
Reactant: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of malonic acid monoethyl ester (16.9 g, 128 mmol) in dry THF (200 mL) was cooled to -78° C. under nitrogen, treated dropwise with 130 mL of isopropyl magnesium chloride (2.0M in THF; 260 mmol), and stirred at -78° C. for 45 minutes. A solution of 3-(4-nitrophenyl)propanoyl chloride prepared in Example EE (13.5 g, 64 mmol) in dry THF (100 mL) was added dropwise. When addition was complete, the reaction mixture was stirred at -78° C. for 1 hour and then allowed to warm to room temperature, where the solution was stirred for 3 more hours. A mixture of ice (50 mL) and 3N HCl (100 mL) was added. The solution was extracted with EtOAc, and the combined extracts were washed with brine and dried (MgSO4). Concentration gave the title compound. 1H NMR (CDCl3) δ 1.21 (t, 3 H), 2.88-3.00 (m, 4 H), 3.40 (s, 2 H), 4.13 (q, 2 H), 7.3 (d, 2 H), 8.09 (d, 2 H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][N:7]=1>C(OCC)(=O)C>[CH3:5][C:6]1[S:10][C:9]([N:11]=[C:1]=[O:2])=[N:8][N:7]=1
Reactant: Cc1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methyl-2-amino-1,3,4 -thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[OH-].[Na+].[Br:9][C:10]1[S:14][C:13]([CH:15]=O)=[CH:12][CH:11]=1>C(O)C>[Br:9][C:10]1[S:14][C:13]([CH:15]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccc(Br)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.6 %

Procedure:
A solution of pyruvic acid (12.1 mL, 174.4 mmol) in ethanol (15.0 mL) was added to a 0.5 M sodium hydroxide solution (476.2 mL). The reaction mixture was stirred at room temperature for 20 minutes. A solution of 5-bromo-thiophen-2-carbaldehyde (30.3 g, 158.6 mmol) in ethanol (140.0 mL) was slowly added to the reaction mixture at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then the precipitate solid was filtered. The resulting solid was washed with diethyl ether, acidified by a 3N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 39.6 g of the titled compound as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[Cl:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:39][C:38]=1[Cl:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(Cl)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Yield: 53.8 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.00 g, 2.49 mmol), (4-(benzyloxy)-3-chlorophenyl)boronic acid (1.31 g, 4.97 mmol), copper(II) acetate (0.903 g, 4.97 mmol), and triethylamine (2.00 mL, 14.4 mmol) in anhydrous DCM (25 mL) was treated with powdered 3 angstrom molecular sieves (2.00 g). The resulting mixture was stirred at RT under air using a drying tube to exclude moisture. After 18 hours the mixture was treated with an additional 1.00 g portion of (4-(benzyloxy)-3-chlorophenyl)boronic acid. After another 18 hours the mixture was diluted with 15 mL of DCM and treated with 1.30 g of (4-(benzyloxy)-3-chlorophenyl)boronic acid, 0.900 g of copper(II) acetate, 2.00 g of 3 angstrom molecular sieves and 2 mL of triethylamine. After 16 more hours the mixture was filtered through Celite to remove solids and the filtrate concentrated to dryness at reduced pressure. The residue was suspended in EtOAc and the undissolved solids removed by filtration through Celite. The filtrate was washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient from DCM to 7:3 DCM/EtOAc) followed by recrystallization from hexane/EtOAc to afford the title compound (0.83 g, 54%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40-8.47 (m, 1H) 8.20 (s, 1H) 7.93-8.00 (m, 2H) 7.69 (d, J=2.6 Hz, 1H) 7.52 (dd, J=8.9, 2.7 Hz, 1H) 7.30-7.48 (m, 7H) 7.25 (d, J=9.1 Hz, 1H) 7.14 (s, 1H) 5.21 (s, 2H) 3.33 (s, 3H) 2.82 (d, J=4.6 Hz, 3H) 2.17-2.33 (m, 1H) 0.75-1.09 (m, 3H) 0.42 (br. s., 1H). LCMS (m/z, ES+)=619, 621 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](Cl)=[O:8].Cl.[CH3:11][NH:12][O:13][CH3:14].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7]([C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:8]
Reactant: CNOC
Reactant: Cc1ncoc1C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ocnc1C
Temperature: 25 °C

Procedure:
4-Methyl-5-oxazolecarbonyl chloride (15 g) and N,O-dimethylhydroxylamine hydrochloride (11 g) in dry chloroform (100 ml) were cooled to 0° C. and dry pyridine (28.5 g) was added. The mixture was allowed to warm to room temperature. After 30 minutes aqueous sodium hydrogen carbonate was added and the organic layer separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed, dried and evaporated. The residue was purified by flash chromatography to yield the title compound as a white solid. M.p. 59°-60° C.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:16][CH3:17])=[O:9])[N:7]=1
Reactant: Nc1nc(C(=O)O)cs1
Reactant: CCO
Agent: Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1csc(N)n1

Procedure:
2-Aminothiazole-4-carboxylic acid hydrobromide (10 g) (E. C. Roberts and Y. F. Shealy, J. Med. Chem. 15 (1972)1310-1312) in ethanol (35 ml) was treated with conc. sulfuric acid and refluxed for 48 hours. The solution was evaporated to 25% of original volume and water (20 ml) added. It was made basic by addition of NaHCO3, the solid filtered, washed with water and dried under vacuum to give the title compound (5.64 g). NMR δ(CDCl3) 137 (3H,t), 4.36(2H,q), 5.39(2H, broad), 7.43(1H,s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH2:9]([S-:11])[CH3:10].[Na+].C(O)CO>[Cu]>[CH2:9]([S:11][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:10]
Reactant: CC[S-]
Reactant: Nc1ccc(I)cn1
Agent: [Cu]
Agent: [Na+]
Solvent: OCCO
Product: CCSc1ccc(N)nc1
Temperature: 150 °C
Reaction time: 26 h
Yield: 77.8 %

Procedure:
2-Amino-5-iodo-pyridine (2.20 g; 10 mmol), sodium ethanethiolate 80% (1.7 g; 16 mmol) and copper powder (190 mg; 3.00 mmol) were loaded into a 100 mL round bottom flask under nitrogen. Ethylene glycol (40 mL; 0.25 mol) was added and the solution stirred at 150° C. for 26 h. The cooled solution was filtered and partitioned between ethyl acetate and water twice. The organic layer was dried over barium oxide, filtered and the solvent removed in vacuo to afford 1.2 g (yield 76%) of product as yellow oil. 1H-NMR (300 MHz; CDCl3), δ 8.06 (1H, d, 4JHH=2.1 Hz, Ar—H), 7.48 (1H, dd, 3JHH=8.7 Hz, 4JHH=2.4 Hz, Ar—H), 6.42 (1H, dd, 3JHH=8.7 Hz, 5JHH=0.6 Hz, Ar—H), 2.68 (2H, q, 3JHH=7.3 Hz, CH2), 1.15 (3H, t, 3JHH=7.2 Hz, CH3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1>[CH2:14]([N:3]1[C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:5]=[CH:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ncn(Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
Part A: To a magnetically stirred suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (15.42 gram, 0.100 mol) in anhydrous THF was slowly added sodium hydride (NaH) (4.88 g of a 60% suspension, 0.120 mol) and the resulting mixture was stirred at room temperature for 30 minutes. Benzyl bromide (13.8 ml, 0.120 mol) was slowly added and the resulting mixture was reacted for 16 hours. Water was added to the mixture. The organic layer was separated from the water layer. The water layer was extracted 3 times with ethylacetate. The organic layer was dried over MgSO4, filtered and thoroughly concentrated to give an oil. The resulting residue was purified (in order to separate the two formed regioisomers) by flash chromatography (diethyl ether/ethyl acetate gradient) to give ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (11.4 gram, 47% yield). 1H-NMR (400 MHz, CDCl3): 1.40 (t, J=7, 3H), 2.45 (s, 3H), 4.37 (q, J=7, 2H), 5.10 (s, 2H), 7.03-7.08 (m, 2H), 7.28-7.38 (m, 3H), 7.48 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (18 mg, 50 μmol) in dichloromethane (2 ml) was added triethylamine (100 μl), followed by cyclopropanecarbonyl chloride (15 mg, 150 μmol). The stirring was continued for 20 min at r.t., then the solvent was removed under reduced pressure, and the product purified by semi-preparative HPLC. Yield 20 mg (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16](=S)[CH2:17][C:18](=O)[CH3:19])[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:10])=[O:9].[C:26]1([CH2:32][CH2:33][CH2:34][NH:35][NH2:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:25][O:24][C:22]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:15][N:14]1[C:16]1[N:35]([CH2:34][CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:36]=[C:18]([CH3:19])[CH:17]=1)=[O:23]
Reactant: NNCCCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1CCCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with 1-(3-phenylpropyl)hydrazine (CAS Reg. No. 3381-02-0) to give the title compound as yellow oil. MS (ESI): m/z=502.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O.Cl>O.C1COCC1>[C:9]([NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:13][CH:12]([CH3:15])[CH3:14])([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:8]
Reactant: NCC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 248.9 %

Procedure:
18.8 g (0.25 mole) Glycine 18 was suspended in 250 ml H2O and 11 g (0.275 mole) NaOH was added. The clear solution was cooled to <10° C. and a solution of 60 g (0.165 mole) (BOC)2O in 250 ml THF was added dropwise keeping T<10° C. (20 minutes). After stirring for 20 hours at room temperature the mixture was acidified to pH1 by adding 1N HCl. The mixture was extracted with EtOAc (250, 100 and 100 ml), the combined organic layers were dried on MgSO4 and evaporated, yielding 47.5 g (>100%) 5 as a colourless oil which contained some THF but was used as such.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([C:11]([F:10])([F:21])[F:22])=[CH:13][CH:14]=2)=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9]
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 14.4 g. (0.12 mole) of 1-methylpyrrole-2-acetonitrile and 25 g. (0.12 mole) of p-trifluoromethylbenzoyl chloride in 120 ml. methylene chloride is chilled to -25°C. (external bath). Then 14 ml. (0.12 mole) stannic chloride is added dropwise over a half hour. The resultant suspension is permitted to come to room temperature and then poured into ice-dilute hydrochloric acid. The aqueous phase is separated and washed successively with N,N-dimethyl-1,3-propane-diamine, 3N hydrochloric acid and a saturated solution of sodium chloride. The solvent is evaporated and the product is isolated from the residual oil by column chromatography using acid washed alumina. The solvents hexane, benzene, and other are used as eluents. The first compound-bearing fraction not giving a positive Enrlich's test (in benzene) is collected. The solvent is evaporated and the resultant solid, 1-methyl-5-(p-trifluoromethyl-benzoyl)-pyrrole-2-acetonitrile, in purified by recrystallization in isopropanol, m.p. 95°-97.5°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>C(OCC)(=O)C>[ClH:21].[ClH:21].[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(OC2CCNCC2)nc1

Procedure:
1-t-Butoxycarbonyl-4-(2-pyridoxy)piperidine (6.5 g) was treated with a solution of hydrogen chloride in ethyl acetate (110 ml) for 7 h and the mixture evaporated to give 4-(2-pyridoxy)piperidine dihydrochloride, (7.4 g 90%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28].[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])=[C:3]([O:23][CH3:24])[CH:4]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(OCCN(C)C)c(OC)c1)O2
Reaction time: 6 h
Yield: 61.3 %

Procedure:
15 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofurane("Dehydrodiisoeugenol") are dissolved in 150 ml abs. toluene at 80° . 9.5 g of N,N-dimethyl-2-chloroethylamine-hydrochloride and 15.5 g KOH in solid form are added. After 6 h at 80°, the solution is cooled down and decanted from solid KOH, whereafter the toluene solution is washed with water to remove dissolved KOH. After drying over sodium sulfate, the solution is evaporated in vacuo. The residue is cristallized in vacuo, and the still present non-cristalline part is dissolved in petroleum ether. One obtains 11.2 g of N-2-[4-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenylbenzofurane-2-yl)-2-methoxyphenoxy]ethyl-N,N,-dimethylamine, as slightly yellow cristals of mp 58°-60° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@H:23]([CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 73 as a pale yellowish solid; mp 173-175° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45-1.60 (m, 2H), 1.90-2.15 (m, 2H), 2.10-2.95 (m, 5H), 3.03 (brd, J=10.5 Hz, 1H), 3.26 (dd, J=14.1, 3.8 Hz, 1H), 3.68 (brd, J=12.4 Hz, 2H), 3.95-4.05 (m, 3H), 4.51 (dd, J=10.0, 4.0 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.75-6.95 (m, 3H), 7.05 (d, J=8.7 Hz, 2H), 11.60 (s, 1H), 11.85 (brs, 1H); MS (ES) m/z: 512.0 (MH+); HRMS Calcd. for C25H30N5O5S (MH+): 512.1968. Found: 512.1982.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6]([C:12]#[N:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1C=C(O[C:21](OC2N=CC=CC=2)=[S:22])N=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:12]([C:6]1[C:5]2[C:9](=[C:10]([CH3:11])[C:2]([N:1]=[C:21]=[S:22])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)#[N:13]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)ccc2c(C#N)c[nH]c12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c(C#N)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 6-amino-3-cyano-7-methylindole (0.155 g, 0.905 mmol) in methylene chloride (10 mL) is added di-2-pyridyl thionocarbonate (0.210 g, 0.905 mmol) followed by 4-dimethylaminopyridine (0.010 g, 0.0905 mmol). The resulting solution is stirred at room temperature for one hour followed by removal of the methylene chloride by rotary evaporation. The crude material is purified via silica gel column chromatography using 20% ethyl acetate/hexane as the eluting solvent. The product containing fractions are combined and the solvents removed by rotary evaporation to yield 0.154 g of 3-cyano-6-isothiocyanato-7-methylindole as a yellow solid (80% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:19]([O-])([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCC(=O)Nc1ccc(C)cc1C(=O)OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1c(C(=O)OC)cc(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 60 %

Procedure:
To a mixture of methyl 5-methyl-2-valerylaminobenzoate (12.8 g) in acetic anhydride (5.9 g) was added dropwise, while stirring under ice-cooling, fuming nitric acid (6.7 ml), followed by stirring for 3 hours. To the reaction mixture was added ice water, which was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate and water, which was then dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel. Crystals thus obtained were recrystallized from isopropyl ether gave colorless crystals (8.5 g, 60%), m.p. 59-60° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])=[O:5].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].[ClH:22]>C1C=CC=CC=1.CCOCC>[ClH:22].[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])=[O:5])[CH3:18]
Reactant: CC(=O)c1cccc(C)c1NC(=O)CCBr
Reactant: CCNCC
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCN(CC)CCC(=O)Nc1c(C)cccc1C(C)=O

Procedure:
To a solution of 1.5 g of 3-bromo-2'-acetyl-6'-methylpropionanilide in 20 ml of benzene was added 0.8 g of diethylamine at room temperature. The resultant mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue. The residue was dissolved in ether and hydrogen chloride was added to the solution to give crystals. Recrystallization from ethanol gave 3-(diethylamino)-2'-acetyl-6'-methylpropionanilide hydrochloride having a melting point of 124° to 126° C.