Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:13]([CH3:15])[CH3:14])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:16](#[N:18])[CH3:17]>>[OH:9][CH:8]([C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH:13]([CH3:15])[CH3:14])[CH:6]=1)[CH2:17][C:16]#[N:18]
Reactant: CC#N
Reactant: CC(C)C(O)COc1cccc(C=O)c1
Product: CC(C)C(O)COc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to benzaldehyde 135 following the method used in Example 34 gave 3-hydroxy-3-(3-(2-hydroxy-3-methylbutoxy)phenyl)propanenitrile (136) as a yellow oil. Yield (0.72 g, 55%): 1H NMR (400 MHz, CDCl3) δ 7.29-7.34 (m, 1H), 6.96-7.0 (m, 2H), 6.89 (dd, J=8.2, 2.0 Hz, 1H), 5.0-5.05 (m, 1H), 4.05 (dd, J=9.2, 2.8 Hz, 1H), 3.92 (dd like t, J=8.4 Hz, 1H), 3.72-3.76 (m, 1H), 2.77 (d, J=6.0 Hz, 2H), 2.44 (d, J=3.6 Hz, 1H), 2.25 (d, J=3.6 Hz, 1H), 1.84-1.93 (m, 1H), 1.04 (d, J=6.8 Hz, 3H), 1.0 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].CCN(CC)CC.C(Cl)Cl>C1COCC1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:2]([O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:3])[CH2:24][CH2:23]2)=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (0.515 mL, 3.61 mmol) was added to a mixture of 1-(4-nitrophenyl)piperazine hydrochloride (0.800 g, 3.28 mmol) and Et3N (1.14 mL, 8.21 mmol) in THF (20 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. DCM (40 mL) was added and the organics were washed with saturated NaHCO3 (40 mL), water (40 mL) then dried over MgSO4. The volatiles removed in vacuo to give the title compound I3 as a yellow solid (1.11 g, 99%); 1H NMR (400 MHz, CDCl3) δ 8.04-8.01 (m, 2H), 7.32-7.18 (m, obscured), 7.15 (s, 1H), 6.72-6.69 (m, 2H), 5.06 (s, 2H), 3.62-3.54 (m, 4H), 3.37-3.26 (m, 4H).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:16]=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:25]([OH:27])=[O:26])=[CH:13][N:14]2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])=[CH:9][C:8]=1[F:29].[N+:30]([O-])([O-:32])=[O:31].[K+]>>[Cl:6][C:7]1[N:16]=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:25]([OH:27])=[O:26])=[CH:13][N:14]2[C:17]2[CH:22]=[C:21]([N+:30]([O-:32])=[O:31])[C:20]([F:23])=[CH:19][C:18]=2[F:24])=[CH:9][C:8]=1[F:29]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To 25 ml of conc. sulfuric acid was added 6.0 grams of 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid. With ice cooling and stirring, to the solution was added 5.0 g of potassium nitrate in portions. The temperature was slowly elevated to 80° C. at which stirring was continued for 2 hours. The reaction solution was allowed to cool, poured into 200 g of ice water, and allowed to stand overnight. The precipitate was collected by filtration, washed with distilled water, ethanol and diisopropyl ether, and air dried, to give 6.4 g of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH:34]C=O)[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]3[S:20][CH:21]=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]>CO.O1CCCC1>[CH2:2]([O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]3[S:20][CH:21]=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.4 %

Procedure:
Conc. hydrochloric acid (0.85 g.) was added under ice-cooling to a stirred solution of 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.3 g) in a mixture of methanol (23 ml.) and tetrahydrofuran (23 ml.), and the mixture was stirred for 2.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate (pH 7.0). The aqueous solution was washed with ethyl acetate and adjusted to pH 3.5 with conc. hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give powder of 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.865 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:10](Cl)=[O:11].O>O1CCCC1>[CH3:16][N:15]([CH3:17])[C:13]([N:9]([CH3:8])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])=[O:14]
Reactant: Nc1ccccc1
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 146.9 %

Procedure:
Into 50 ml of anhydrous tetrahydrofuran, 7.4 g (0.08 mol) of aniline was added thereinto and dissolved and the mixture was cooled below 0° C. under stirring. Into this cooled mixture, a solution obtained by dissolving 6.4 g (0.04 mol) of 2,4,4-trimethylallophanoyl chloride in 10 ml of anhydrous tetrahydrofuran was added drop-wise under stirring. After the reaction was continued for 1 hour at room temperature, the solvent was remvoed by distillation under reduced pressure. To the residue thus obtained, water was added and insoluble material was separated by filtration and was recrystallized from ethanol to obtain 13.0 g (yield: 73%) of 1,1,3-trimethyl-5-phenylbiuret having a melting point of 89.5°-90.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8]O)[N:5]=[CH:4][C:3]=1[C:10]#[N:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32].CCOC(C)=O>ClCCl>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][Cl:32])[N:5]=[CH:4][C:3]=1[C:10]#[N:11]
Reactant: N#Cc1cnn(CCO)c1N
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1cnn(CCCl)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 5-amino-4-cyano-1-(2hydroxyethyl)pyrazole (40 g.) and triphenylphosphine (82.7 g.) in dichloromethane (300 ml.) was cooled in a room temperature water bath while carbon tetrachloride (127 ml.) was added dropwise over 45 minutes. The resulting suspension was stirred at room temperature under nitrogen overnight, and the volatiles were then removed on a rotary evaporator, leaving an orange semisolid. This was treated with boiling EtOAc (500 ml.), chilled at 0° , filtered, and the filtrate evaporated to dryness. The residue was redissolved in THF (300 ml.) and evaporated onto flash silica gel (160 g.). This material was placed atop a column of flash silica gel (300 g.) and the desired product eluted with EtOAc/hexane (1:1 v/v). Contaminating triphenylphosphine oxide was removed by trituration with dichloromethane/hexane (1:1 v/v). The remaining solid was then recrystallized from EtOAc to give 5-amino-1-(2-chloroethyl)-4-cyanopyrazole (29.07 g.) as white crystals: m.p. 155.5-156.5 °.
Reaction SMILES: [CH3:1][C@@H:2]([CH:22]([OH:24])[CH3:23])[CH:3]1[O:5][CH:4]1[CH2:6][C@H:7]1[C@H:12]([OH:13])[C@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=[O:19])[O:9][CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[K+].[Se-]C#N.[K+].C(O)(CC)(C)C.O>COC(OC)(C)C.C(OCC)(=O)C>[CH3:1][C@@H:2]([C@@H:22]([OH:24])[CH3:23])[C:3]1[O:5][C:4]=1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=[O:19])[O:9][CH2:8]1
Reactant: C/C(=C\C(=O)O)C[C@@H]1OC[C@@H](CC2OC2[C@@H](C)C(C)O)[C@H](O)[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#C[Se-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCC(C)(C)O
Solvent: O
Product: C/C(=C\C(=O)O)C[C@@H]1OC[C@H](CC2=C([C@@H](C)[C@H](C)O)O2)[C@@H](O)[C@H]1O

Procedure:
Monic acid A (3.44 g) was dissolved in 2,2-dimethoxypropane (30 ml) and ethyl acetate (30 ml) with a few crystals of p-toluene sulphonic acid. After one hour the solution was diluted with ethyl acetate and washed with brine then dried (MgSO4). The solvent was removed in vacuo and the acetonide dissolved in water-methanol (1:1, 40 ml) then treated with potassium bicarbonate (1.0 g, 1 eq). The solution was evaporated to dryness and potassium selenocyanate (4.32 g, 3 eq), tert-amyl alcohol-water (9:1, 150 ml) added and reaction refluxed for 42 hours. After filtering, the reaction mixture was diluted with ethyl acetate and extracted with water (4×25 ml). The combined aqueous phases were acidified (pH2, 5 M-HCl) and extracted with ethyl acetate (4×25 ml) and the combined extracts dried (MgSO4). The solvent was removed in vacuo to give 6,7-O-ispropylidene monic acid C, νmax (CHCl3) 1695, 1640, 1380, 1370, 1220 and 1055 cm-1 ; δ H (CDCl3) 0.98 (3H, d, CH3 -17), 1.13 (3H, d, CH3 -14), 1.33 and 1.48 (6H, d, acetonide CH3 's), 2.17 (3H, s, CH3 -15), 5.45 (2H, m, H-10, H-11), 5.75 (1H, s, H-2), 4.35 (2H, broad, CO2H, OH); δC (CDCl3) 170.5 (C1), 158.3 (C3), 134.9, 128.8 (C10, C11), 117.5 (C2), ##STR7## 76.5 (C5), 75.7 (C7), 74.1 (C6), 71.1 (C13), 66.5 (C16), 44.3 (C12), 36.8 (C8), 34.1 (C9), 28.3, 26.3 (C(CH3)2), 20.1 (C14), 19.3 (C15), 16.3 (C17); m/e (relative intensity) 353 (9) (Found: 353.1995. M+ --CH3 requires 353.2026) 350 (4) (M+ --H2O). The acetonide was dissolved in 80% acetic acid (100 ml) then left overnight. The solution was evaporated to dryness and chromatographed on silica (50 g) eluting with 0-10% methanol-chloroform. The fractions containing pure product (tlc) were combined and evaporated to give monic acid C m.p. 101°-102° C. (2.57 g, 72%) (Found: C, 61.8; H, 8.4. C17H28O6 requires C, 62.2; H, 8.6%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.CCO>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15]
Reactant: [O-][n+]1ccccc1Cl
Reactant: NCCCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)(C)O
Product: [O-][n+]1ccccc1NCCCCO
Reaction time: 48 h

Procedure:
A mixture of 4-amino-1-butanol (1.76 g, 20 mmol), 2-chloropyridine N-oxide hydrochloride (3.98 g, 24 mmol), and NaHCO3 (8.40 g, 100 mmol) in tert-amyl alcohol (50 mL) is heated at reflux under argon. After 48 h, the reaction is cooled, diluted with EtOH, filtered, and concentrated. The residue is reconcentrated from toluene, and chromatographed (silica gel) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COC(=O)C=CC(NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCC(NC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of methyl 4-[(t-butoxycarbonyl)-amino]-4-phenylbut-2-enoate (3.17 g) in methanol (100 mL) was added palladium on carbon (250 mg (10% by wt. Pd)). The mixture was then placed under 50 psig hydrogen gas, and was shaken on a Parr hydrogenator for 2 hours. The mixture was then filtered through celite, concentrated in vacuo and purified by silica gel flash chromatography (3:1 hexanes:ethyl acetate) to afford methyl 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanoate as a pale yellow oil in a yield of 2.61 g (82%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.07 (m, 2H), 2.36 (m, 2H), 3.69 (s, 3H), 4.59 (m, 1H), 5.15 (br s, 1H (NH)), 7.21-7.34 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=[O:9])[N:5]=[C:4]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH:3]=1.[OH:18]OS([O-])=O.[K+]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])(=[O:18])=[O:9])[N:5]=[C:4]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH:3]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)=O)n2)[nH]n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred suspension of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfinyl)pyrimidin-4-amine (8 g, 31.2 mmol) in methanol (200 ml) at 0° C. was added a suspension of Oxone (44 g, 71.7 mmol) in water (100 ml) portionwise over 10 minutes. The mixture was stirred for 30 minutes at 0° C. then warmed to ambient and stirred for an additional 2 hours. The reaction mixture was filtered and the resulting solid slurried in aqueous sodium bicarbonate. The mixture was filtered and the solid washed with water, then diethyl ether. The solid was slurried in ethyl acetate, filtered and dried. This gave the title product as an off-white solid (7.9 g, 88%); 1H NMR (d6-DMSO) δ 2.24 (3H, s), 3.35 (3H, s), 5.85 (0.5H, brs), 6.50 (0.5H, brs), 6.95 (0.5H, brs), 8.00 (0.5H, brs), 10.95 (1H, s), 12.28 (1H, s); MS ES+ 288.07, ES− 286.25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Br)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH3:10]
Reactant: Oc1ccccc1Br
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
8.65 g of bromophenol and 8.75 g of 4-bromobutyric acid ethyl ester are dissolved in 120 ml of dimethylformamide, mixed with 32.6 g of cesium carbonate and stirred for 2 days at room temperature. The reaction mixture is filtered, the solvent is distilled off in a vacuum and the residue is distilled in a bulb tube at 180° C./0.4 mbar. 11 g of 4-(2-bromophenoxy)butyric acid ethyl ester is obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1>[Ni].CO>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1
Yield: 100 %

Procedure:
Raney nickel (2 g) was added to a solution of 4-trifluoromethylphenylhydrazine (1 g) in methanol (5 ml) and heated at reflux for 1 hour. The cooled mixture was filtered and evaporated to give the title compound in 100% yield.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:19])[CH:13]=2)[N:8]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:19])[CH:13]=2)[N:8]=1
Reactant: COc1ccc(CNc2nc3ccc(C)cc3nc2OC)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc2cc(C)ccc2nc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To 2-(2,4-dimethoxybenzylamino)-3-methoxy-6-methylquinoxaline (4.48 g, 13.2 mmol), 30 ml of 50% trifluoroacetic acid in dichloromethane was added at room temperature. The resulting mixture was stirred at room temperature for 18 hours and concentrated under the reduced pressure to remove the solvent. The residue was neutralized with saturated sodium bicarbonate solution and then NaCl solution was added thereto. The product was extracted with dichloromethane and the organic layer was dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 2.01 g of the titled compound (yield, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10](O)[C:9]1=[O:21].C(Cl)(=O)C([Cl:25])=O>CN(C=O)C>[Cl:25][C:10]1[C:9](=[O:21])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12](=[O:13])[C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1c1ccccc1Cl
Reaction time: 0.5 h

Procedure:
After dissolving compound 6b (3.00 g, 10.0 mmol) in MC (10 ml) and anhydrous DMF (10 ml), oxalyl chloride (2.50 g, 20.0 mmoL) was added thereto and the agitation for 30 minutes was carried out. After the identification of the reaction progress with TLC, the reaction was terminated. Then, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using anhydrous Na2SO4, solvents were removed and then, the column chromatography was carried out with EA/HX ( 1/15). The suspension was carried out with HX to obtain compound 7b.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:19]#[N:20].O.Cl>CN(C)C=O.[Fe](Cl)Cl>[C:19]([C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1)#[N:20]
Reactant: Brc1cccc(CCOCCc2ccsc2)c1
Reactant: N#C[Cu]C#N
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(CCOCCc2ccsc2)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
46 mg of the resulting ether compound was dissolved in 1 ml of dimethylformamide, and 17 mg of copper cyanide was added. The mixture was stirred overnight at 150° C. To this solution was added, a mixture of 39 mg of iron(II) chloride, 0.1 ml of water and 16 μl of hydrochloric acid, and the mixture was stirred at 60° C. for 30 minutes. The solution was extracted with ethyl ether, and the extract was worked up in a customary manner to give 17 mg of 3-[2-[2-(3cyanophenyl)ethoxy]ethyl]thiophene as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][OH:33]>C(O)CCC>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][O:33][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CN(C)CCOc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline, (100, 0.293), triethylamine (123 μL, 0.879 mmol), N,N-dimethylethanolamine (959 μL, 0.586 mmol) in n-butanol (3.0 mL) was heated in the microwave at 120° C. for 20 minutes, then concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluting with chloroform/7 N ammonia in methanol (0.1-5%) to afford the title compound (75 mg, 74%).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[C:11]([S:19][CH3:20])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>ClC1C=CC=CC=1Cl>[CH2:9]([O:8][C:6]([C:5]1[C:11]([S:19][CH3:20])=[N:12][C:13]2[C:14]([C:4]=1[OH:21])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)=C(Nc1ccccc1)SC
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1c(SC)nc2ccccc2c1O
Yield: 34.9 %

Procedure:
A mixture of 2-(methylsulfanyl-phenylamino-methylene)-malonic acid diethyl ester (27 g, 87 mmol) in 1,2-dichlorobenzene (100 mL) was heated to reflux for 1.5 h. The solvent was removed under reduced pressure and the oily residue was triturated with hexane to afford a pale yellow solid that was purified by preparative HPLC to yield 4-hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid ethyl ester (8 g, 35%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:17])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Product: O=C(NCc1ccccc1)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and benzyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>O1CCOCC1>[CH3:11][C:10]1[C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: C1COCCO1
Product: Cc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (6 g) in dry 1,4-dioxane (50 mL) was added dropwise a solution of trichloromethyl chloroformate (8 mL) in dry 1,4-dioxane (25 mL), with ice-water cooling to keep the reaction temperature below 25° C. A white precipitate began to form during the addition. The reaction mixture was stirred at room temperature overnight. The precipitated solids were removed by filtration and washed with 1,4-dioxane (2×20 mL) and hexane (2×15 mL) and air-dried to yield 6.51 g of off-white solid.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][N:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=4)[CH3:21])=[N:16][C:15]=3[CH:31]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][N:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:29])[NH2:30])=[CH:24][CH:23]=4)[CH3:21])=[N:16][C:15]=3[CH:31]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CN(C)c3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc2s1)c1ccc(C(=N)N)cc1
Yield: 96 %

Procedure:
Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 96% of theory, C26H25N5O3S (487.58) Rf value: 0.48 (Merck RP-8, methanol/5 NaCl solution=6:4) ##EQU2##
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([NH:13][C:14]2([CH2:20][NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:29][C:30](Cl)=[O:31].O>CN(C)C=O>[O:31]=[C:30]1[N:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:29]1
Reactant: CCOC(=O)CNCC1(Nc2ccccc2)CCCCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CC2(CCCCC2)N(c2ccccc2)CC1=O
Yield: 96.5 %

Procedure:
95 mg (0.69 mmol) of potassium carbonate are added to a solution of 200 mg (0.69 mmol) of ethyl [(1-phenylaminocyclohexylmethyl)amino]-acetate and 55 μl (0.69 mmol) of chloroacetyl chloride in 15 ml of dimethylformamide. The reaction medium is stirred at reflux for 6 h and poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. 220 mg of ethyl (3-oxo-1-phenyl-1,4-diazaspiro[5.5]undec-4-yl)acetate are obtained in the form of an orange oil. Yield=97%.