Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:18])[NH:13]2)([OH:3])=O.CN1CCOCC1.ClC(OC)=O.[CH2:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]>O.C(Cl)Cl>[CH2:31]([N:33]([C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:18])[NH:13]2)=[O:3])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: CCNc1ccccc1
Reactant: O=C(O)CCCOc1cccc2c1CCC(=O)N2
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CCN(C(=O)CCCOc1cccc2c1CCC(=O)N2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.5 Grams of 5-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 2.0 ml of N-methylmorpholine are added to 200 ml of methylene chloride, and then 1.0 ml of methyl chloroformate is added dropwise to said solution under external ice cooling and agitation while maintaining the internal temperature at 10°-20° C. After this dropwise addition, the mixture is further agitated at room temperature for 30 minutes and then added with 1.3 ml of N-ethylaniline, followed by additional 4-hour agitation at the same temperature. After the reaction, the reaction solution is added with water, and after liquid separation, the organic layer is washed with a dilute aqueous NaOH solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na2SO4. After filtering out the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ethanol, consequently obtaining 2.6 g of 5-[3-(N-ethylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. m.p. 179.5°-180.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH2:7][NH2:8].N1C=CC=CC=1.[C:36]([NH:39][CH2:40][CH2:41][NH2:42])(=[O:38])[CH3:37].[CH3:43][OH:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][CH:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:16][CH:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH2:7][NH:8][C:43](=[O:44])[NH:42][CH2:41][CH2:40][NH:39][C:36](=[O:38])[CH3:37]
Reactant: CO
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN
Reactant: CC(=O)NCCN
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCNC(=O)NCc1cc(Cl)ccc1OCC(=O)N1CC(C)N(Cc2ccc(F)cc2)CC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamine (0.200 g, 0.477 mmol) in methylene chloride (10 mL) was added pyridine (0.077 mL, 0.954 mmol) and 4-nitro phenyl chloroformate (0.097 g, 0.525 mmol). The resulting mixture was stirred for one hour at ambient temperature and then concentrated in vacuo. The residue (0.055 g, 0.094 mmol) was dissolved in methanol (1 mL). N-Acetylethylenediamine (0.019 mL, 0.188 mmol) was added and the reaction was stirred at room temperature over night. The reaction was concentrated in vacuo and chromatography on silica gel gave the title compound (0.019 g, 27%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:17][C:9]2[CH:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:27]1[N:32]=[N:31][C:30]([C:33]([OH:35])=O)=[CH:29][CH:28]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[CH2:36]([NH2:42])[C:37]1[O:41][CH:40]=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:27]3[N:32]=[N:31][C:30]([C:33]([NH:42][CH2:36][C:37]4[O:41][CH:40]=[CH:39][CH:38]=4)=[O:35])=[CH:29][CH:28]=3)[C:8]3[C:15](=[O:16])[N:14]4[CH:10]([CH2:11][CH2:12][CH2:13]4)[C:9]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)nn1)C(=O)N1CCCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)nn1)C(=O)N1CCCC21
Reaction time: 2 h

Procedure:
The mixture of 6-[3-(ethoxycarbonyl)-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]-3-pyridazinecarboxylic acid (G, 33 mg, 0.07 mmol), furfurylamine (19.3 mmol, 0.14 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.7 mg, 0.14 mmol) and 1-hydroxybenzotriazole hydrate (18.8 mg, 0.14 mmol) in 2 ml dichloromethane was stirred for 2 hours. The mixture was then partitioned between water and ethyl acetate. The organic was washed with brine and dried over sodium sulfate. The residue upon the removal of the solvent was purified with flash chromatography. Twelve (12) mg white solid was obtained. NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 8.08 (d, 1H), 7.20 (t, 2H), 6.92 (t, 2H), 4.78 (m, 1H), 4.67 (d, 2H), 4.40 (dd, 2H), 3.90 (q, 2H), 3.64 (m, 1H), 3.39 (m, 1H), 2.48 (m, 1H), 2.35 (m, 2H), 1.40 (m, 1H), 0.90 (t, 3H) ppm. ESI-MS m/z 556 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[N:17]=[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:19][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:20]1[S:19][C:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:17][C:16]=1[CH3:15])=[O:22]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)Cl
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)sc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 75.1 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0452 g, 0.192 mmol), 4-methyl-2-phenylthiazole-5-carbonyl chloride (0.047 g; 0.192 mmol), and triethylamine (0.067 mL; 0.479 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 3 to 30% of ethyl acetate in dichloromethane gave 0.0571 g (75%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-methyl-2-phenylthiazole-5-carboxamide as a solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:23][C:24](=[O:26])[CH3:25])[CH:9]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=3)[CH:11]=2)=[CH:4][N:3]=[CH:2]1.[Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.C1C(=O)N([Br:54])C(=O)C1>C1COCC1>[Br:54][C:2]1[S:1][C:5]([C:6]2[CH:7]=[C:8]([NH:23][C:24](=[O:26])[CH3:25])[CH:9]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][N:14]=3)[CH:11]=2)=[CH:4][N:3]=1
Reactant: CC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(Br)s2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 0 %

Procedure:
A microwave vial containing N-[3-(1,3-thiazol-5-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]acetamide (50 mg, 0.132 mmol) in THF (659 μL) was cooled to −78° C. in a dry ice-acetone bath. To the solution was added a stock solution of LDA prepared from the addition of n-BuLi (3.47 μL, 1.52 M, 0.527 mmol) over diisopropylamine (54.7 mg, 0.540) in THF at −78° C. After stirring the suspension for 20 minutes, a solution of NBS (94 mg, 0.527 mmol) in THF (1 mL) was added. The resulting yellow suspension was stirred at −78° C. for 1 h, after which the bath was removed. Once at room temperature, the reaction was treated with sat. NaHCO3(aq) and the phases were separated. The aqueous was extracted 3 times with ethyl acetate. Organic layers were combined, washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. The residual solid was purified by flash chromatography to yield N-[3-(2-bromo-1,3-thiazol-5-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-acetamide as a beige powder (29 mg, 0.063 nmol, 48%).
Reaction SMILES: COC1N=C(C[S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])C([N+]([O-])=O)=CC=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccc(C)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CS(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C

Procedure:
A mixture of 5.0 g (15.5 mmol) of 6-methoxy-3-nitro-2-(toluene-4-sulfonyl methyl)-pyridine and 1.8 mL (16 mmol) of ethyl bromoacetate is dissolved in 20 mL of DMF. To this solution is added 4.4 g (32 mmol) of K2CO3 and the reaction mixture is heated to 50° C. for 18 hours. The reaction mixture is cooled to room temperature and diluted with 300 mL of water. The mixture is extracted with ethyl acetate. The ethyl acetate extracts are dried (Na2SO4) and evaporated to yield 7.2 grams of 6-methoxy-3-nitro-pyridin-2-yl]-[toluene-4-sulfonyl]-acetic acid ethyl ester. 1H NMR (CDCl3) δ 8.30 (d, 1H), 7.60 (d, 2H), 7.30 (d, 2H), 6.80 (d, 1H), 6.30 (m, 1H), 4.0 (q, 2H), 3.80 (s, 3H), 3.60 (m, 1H), 3.10 (m, 1H), 2.40 (s, 3H), 1.10 (t, 3H). Mass spectrum: m/e=409.0 (p+1). TLC (7/3: hexanes/ethyl acetate) Rf=0.5. Step 3:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.CC1N=C(N2CCN(CCCCC)C2=O)SC=1C(O)=O.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>>[CH3:18][C:16]1[N:17]=[C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH2:7][CH2:6][CH3:5])[C:9]2=[O:22])[S:14][C:15]=1[C:19]([NH:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)=[O:21]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: CCCCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: CCCCCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 40 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-pentylimidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 40% yield: mp 102-103° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.54-8.43 (m, 2H), 7.63 (d, J=7.5 Hz, 1H), 7.21-7.17 (m, 1H), 6.50 (br s, 1H), 4.54 (J=5.8 Hz, 2H), 4.05-3.97 (m, 2H), 3.55-3.47 (m, 2H), 3.26-3.14 (m, 2H), 2.55 (s, 3H), 1.52-1.46 (m, 2H), 1.30-1.20 (m, 4H), 0.84 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.4, 153.6, 149.2, 148.8, 135.5, 134.0, 123.6, 116.6, 43.8, 42.1, 42.0, 41.3, 28.8, 26.9, 22.3, 17.3, 14.0; MS (ES+) m/z 388.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][N:7]=1.Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[N:7][CH:6]=1
Reactant: Clc1ncc(-c2ccccc2Cl)nn1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CCN(c2ncc(-c3ccccc3Cl)nn2)CC1

Procedure:
1.5 g of 3-chloro-6-(2-chlorophenyl)-1,2,4-triazine, 3.05 g of piperidin-4-one monohydrate hydrochloride and 3.1 g of sodium carbonate are heated under reflux in 100 ml of ethanol for 4 hours.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]([Cl:16])=[O:15])[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[O:24]1CCC[CH2:25]1>>[CH:17]1([O:23][C:25]([N:10]2[CH2:11][CH2:12][N:8]([C:14]([Cl:16])=[O:15])[C:9]2=[O:13])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCCCC1
Reactant: O=C(Cl)N1CCNC1=O
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)N1CCN(C(=O)OC2CCCCC2)C1=O
Reaction time: 1 h

Procedure:
Triethylamine (5.8 parts by weight) was added dropwise to a mixture of imidazolidin-2-on-1-carbonyl chloride (7.4 parts by weight), tetrahydrofurane (50 parts by volume) and cyclohexanol (5.5 parts by weight) while stirring, and cooling with ice, the mixture was then slowly stirred overnight at room temperature and subsequently boiled for 1 hour under reflux, and the triethylamine hydrochloride was filtered off hot. The filtrate was completely evaporated in vacuo, the residue was triturated with cyclohexane and the solid product was filtered off and dried 3 days in a desiccator. Yield: 5.0 parts by weight. This substance (5.0 parts by weight was then suspended in tetrahydrofurane, triethylamine (5.2 parts by volume) was added, the mixture was boiled under reflux and a solution of trimethylchlorosilane (3.8 parts by weight) in tetrahydrofurane (10 parts by volume) was at the same time added dropwise. Thereafter the mixture was boiled overnight under reflux and insoluble matter was then filtered off hot. A solution of phosgene (2.6 parts by weight) in tetrahydrofurane (10parts by volume) was slowly added to the filtrate at room temperature and the mixture was left to stand well sealed at room temperature for 24 hours. A precipitate which was present (largely triethylamine hydrochloride) was then filtered off and the filtrate was completely evaporated in vacuo. The crystalline residue was dried in a desiccator. The substance has a broad absorption between 1680 and 1820 cm-1 in the carbonyl region of the IR-spectrum (Nujol). It was reacted, in this form, with ampicillin.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[O:26][CH3:27])=O.C(O)(=O)C.N1CCCCC1>ClCCl>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH:16]=[C:6]([C:5](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:13][CH2:14][CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:19]([O:26][CH3:27])[CH:20]=1)#[N:23]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: COc1cc(C#N)ccc1C=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)C(=Cc1ccc(C#N)cc1OC)C(=O)C(OCC)OCC

Procedure:
618.2 mg (2.83 mmol) of ethyl 4,4-diethoxy-3-oxobutanoate [Johnson et al., J. Am. Chem. Soc. 41, 812 (1919)], 500.0 mg (2.58 mmol) of 4-formyl-3-methoxybenzonitrile, 232.0 mg (3.86 mmol) of acetic acid and 43.9 mg (0.51 mmol) of piperidine are dissolved in 20 ml of dichloromethane and heated under reflux with an inverse water trap ovemight. Cooling is followed by washing twice with water, and the organic phase is dried with magnesium sulfate. The solvent is removed in a rotary evaporator, and the residue is purified by column chromatography (silica gel, mobile phase:cyclohexane/ethyl acetate 4:1). 824 mg (77.0% of theory) of the title compound are obtained as a mixture of the E/Z isomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25]1([C:31](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH:8][C:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
L-Tyrosine tert-butyl ester* was reacted at room temperature in DMF, in the presence of triethylamine, with an equimolar amount of triphenylmethylchloride. Through mixing of the DMF phase with the 4-fold amount of ice the raw product is precipitated and recrystallized from ethanol.
Reaction SMILES: [CH:1]1(N(C)C(=S)NN)[CH2:5][CH2:4]CC1.Cl[CH:13]([C:19]([CH3:21])=[O:20])[C:14](OCC)=O.Cl>C(O)C>[CH2:13]([C:19]([CH3:21])=[O:20])[CH3:14].[CH3:13][CH:19]([O:20][CH:5]([CH3:4])[CH3:1])[CH3:21]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CN(C(=S)NN)C1CCCC1
Agent: Cl
Solvent: CCO
Product: CC(C)OC(C)C
Product: CCC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred slurry of 8.4 g (0.049 mole) of 4-cyclopentyl-4-methyl-3-thiosemicarbazide in 50 mL of absolute ethanol was treated with 8.1 g (0.049 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 18 hr, treated with 25 mL of 2N ethanolic hydrogen chloride and heated at reflux for 2 hr. The hot solution was filtered to remove amorphous sulfur and concentrated to a red oil which gave a crude solid product when triturated with acetone. After four recrystallizations; methyl ethyl ketone/2-propyl ether (twice), acetonitrile/acetone and finally from acetonitrile, there was obtained 3.2 g of crystalline product, mp 144°-146° C., as the hydrochloride salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>S1(CCCC1)(=O)=O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: O=S1(=O)CCCC1
Product: CNc1nc(Nc2ccc(Cl)c(Cl)c2)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
6.47 g of 2-chloro-4-methylamino-5-nitro-pyrimidine and 11.7 g of 3,4-dichloro-aniline are heated to 160° C. in 60 ml of sulpholane within 45 minutes in an oil bath. After 40 minutes stirring at this temperature the reaction mixture is cooled and added to 600 ml of ice water. The precipitate is suction filtered, washed repeatedly with water and dried. The residue is stirred for one hour with 100 ml of ethyl acetate, the precipitate is suction filtered, washed with ethyl acetate and dried.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][O:18][CH3:19])[CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C([S-])C.[Na+].CN(C=O)C>C(OCC)(=O)C>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH:12]2[CH:13]([CH2:17][O:18][CH3:19])[C:14]3[CH:15]=[CH:16][C:3]([OH:2])=[CH:4][C:5]=3[CH:6]3[CH:11]2[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:21][CH:22]=1
Reactant: COCC1c2ccc(OC)cc2C2CCCCC2C1c1ccc(OC)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1c2ccc(O)cc2C2CCCCC2C1c1ccc(O)cc1
Reaction time: 18 h
Yield: 31.7 %

Procedure:
Combine 6-methoxy-9-methoxymethyl-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (0.050 g, 0.14 mmol), sodium ethanethiolate (0.037 g, 0.44 mmol), and DMF (4 mL), and reflux under nitrogen atmosphere. After 18 hours, cool the reaction to room temperature and add ethyl acetate, wash with sat ammonium chloride solution (aq), then brine several times. Concentrate, and purify using reverse phase chromatography (5% to 95% 0.001% TFA buffer in acetonitrile/water) to yield the titled compound (0.015 g, 33%) as a white solid. TLC Rf=0.27 in 3:1 hexanes:ethyl acetate. 1H NMR (d-methanol): 7.42 (d, 1H, J=8.4 Hz), 7.13 (d, 2H, J=8.4 Hz), 6.84 (s, 1H), 6.79 (d, 2H, J=8.4 Hz), 6.65 (dd, 1H, J=7.9, 1.8 Hz), 3.70 (d, 1H, J=7.0 Hz), 3.35 (m, 3H), 3.17 (s, 3H), 3.07 (m, 1H), 2.48 (d, 1H, J=14.1 Hz), 1.87 (m, 1H), 1.64 (m, 2H), 1.41 (m, 2H), 1.16 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[F:14][C:15]1[CH:28]=[CH:27][C:18]2[S:19][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([CH3:22])[C:17]=2[CH:16]=1>ClCCl.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][S:23]([C:20]3[S:19][C:18]4[CH:27]=[CH:28][C:15]([F:14])=[CH:16][C:17]=4[C:21]=3[CH3:22])(=[O:25])=[O:24])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: Nc1ccc(-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of (4-pyridine-4-yl)aniline (CAS: 13296-04-3, 0.290 g) in dichloromethane (12.0 ml) was added 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (0.440 g) and DMAP (0.305 g). The reaction mixture was stirred at rt for 16 h, diluted with dichloromethane (12 ml) and chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the title compound (0.205 g) as an off-white solid. MS (ISN): 397.1 (M−H)−
Reaction SMILES: C([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=O)C>Cl>[NH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:6]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Agent: Cl
Product: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Yield: 83 %

Procedure:
A mixture of 2-acetamido-5-chloro-3-nitrobenzotrifluoride (354 mg, 1.252 mmol) in concentrated HCl (3 mL) was refluxed overnight, and it was extracted by ethyl acetate (2×3 mL). The extract was dried (Mg2SO4) and evaporated to give 250 mg (83%) of 2-amino-5-chloro-3-nitrobenzotrifluoride. 1H NMR (CDCl3): δ6.663 (s, 2H), 7.717 (s, 1H), 8.360 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(C[C:18]([CH2:21]C)([O-])[O-:19])C.C[OH:24]>>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:10](=[CH:11][CH:12]=2)[NH:13][C:18](=[O:19])[C:21](=[O:24])[NH:14]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CO
Reactant: Nc1ccc(Cn2ccnc2)cc1N
Reactant: CCCC([O-])([O-])CC
Product: O=c1[nH]c2ccc(Cn3ccnc3)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
A mixture of 5 parts of 4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 4 parts of diethyl ethanedioiate and 40 parts of methanol was stirred for 4 hours at room temperature. The precipitated product was filtered off and dried, yielding 4 parts (62.3%) of 6-(1H-imidazol-1-ylmethyl)-2,3(1H,4H)-quinoxalinedione; mp. >300° C. (comp. 315).
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)N=1)(=[O:5])[CH3:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=1.[CH3:23]O>O>[C:14]1([CH:13]=[CH:4][C:3]([C:6]2[CH:23]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CO
Reactant: CC(=O)c1cccc(Br)n1
Reactant: COc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 76 %

Procedure:
Potassium hydroxide (18.2 g, 325 mmol) was dissolved in 100 mL of H2O, and 100 mL of methanol was added. 2-Acetyl-6-bromopyridine (65 g, 325 mmol) and (68 g, 650 retool) of p-anisaldehyde were dissolved together in 400 mL of methanol, and the solution was poured into the KOH solution. Precipitation of product began Within a few minutes, and the reaction was allowed to stand at room temperature overnight. The precipitate was collected, washed with isopropanol, and dried to yield 79 g (76%) of the product as a yellow solid, mp 100°-102° C. FDMS (m/e) 317M. An aliquot was purified by column chromatography on Woelm Silica gel, elution with 100% dichloromethane. Anal. Calcd for C15H12BrNO2 : C, 56.63; H, 3.80; N, 4.40. Found: C, 6.66;H, 3.87; N, 4.41. The NMR and IR spectra were consistent with the assigned structure and the product was homogeneous by TLC.