Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][NH:15][CH3:16])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][N:15]([CH2:14][CH2:13][NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11])[CH3:16]
Reactant: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 63.4 %

Procedure:
A mixture of 2.44 g (10.0 mmol) of 3,5-diamino-6-chloro-N-(2-methylaminoethyl)pyrazine-2-carboxamide, 1.67 g (10.0 mmol) of methyl 3-bromopropionate and 1.38 g (10.0 mmol) of potassium carbonate was stirred in 20 ml of DMF for 18 hours at ambient temperature. Water (100 ml) was added and the solid was filtered and air dried. Crystallization from ethanol provided 2.1 g (6.34 mmol, 63%) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]-N-methyl-beta-alanine methyl ester as white crystals; mp 136.5°-137° C.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([NH:39][C@H:40]([C:42]([OH:44])=O)[CH3:41])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].[CH:45]1[C:53]2[C:52]3[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:51]=3[O:50][C:49]=2[CH:48]=[CH:47][C:46]=1[NH2:59]>>[CH3:41][C@H:40]([NH:39][C:29](=[O:30])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:42](=[O:44])[NH:59][C:46]1[CH:47]=[CH:48][C:49]2[O:50][C:51]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][C:52]=3[C:53]=2[CH:45]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 13.1 %

Procedure:
Following the procedure of Example 30, triethylamine (0.52 mL, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.37 g, 1.9 mmol), N-hydroxybenzotriazole (0.26 g, 1.9 mmol), N-carbobenzyloxy-L-alanine (0.37 g, 1.6 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.30 g, 1.5 mmol) provided benzyl [(1S)-1-methyl-2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.08 g) after purification by flash column chromatography (elution with 40% ethyl acetate-hexanes). MS (ES) m/z 407.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[CH2:10]([O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[F:9])[CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)c(F)c1
Product: CCCCOc1cccc(-c2ccc(N)cc2F)c1
Yield: 88.5 %

Procedure:
The title compound (241 mg) was prepared from 4-bromo-3-fluoroaniline (200 mg, 1.05 mmol) and 3-butoxyphenylboronic acid (265 mg, 1.4 mmol) as a colourless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5](Br)[CH3:6])[CH3:2].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)Br
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)NCc1ccccc1
Temperature: 20 °C

Procedure:
To a solution of 2-bromo-propionic acid ethyl ester (1 eq.) in MeCN was added benzylamine (0.9 eq.) and potassium carbonate (1.5 eq.). The reaction was refluxed for 4 h then cooled to 20° C. and diluted with EtOAc. The crude was filtered, the filtrate was concentrated under reduced pressure, then purified by chromatography on silica gel (elution with heptane/EtOAc: 7/3) to afford 2-benzylamino-propionic acid ethyl ester.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18]/[CH:19]=[CH:20]\[CH3:21]>C(O)C>[C:2]([NH:5][C:6]([CH2:18]/[CH:19]=[CH:20]\[CH3:21])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: C/C=C\CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: C/C=C\CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Reaction time: 8 h
Yield: 98 %

Procedure:
4.37 g (190 mmol) of sodium metal were dissolved in 110 ml of anhydrousethanol. 41.14 g (189.6 mmol) of diethyl acetamidomalonate dissolved in 270ml of anhydrous ethanol were added and the mixture was heated under reflux for 10 minutes. 25.65 g (168 mmol) of (Z)-1-bromo-2-butene were added dropwise at room temperature and the mixture was stirred overnight, then evaporated to dryness under vacuum and the residue was partitioned betweenethyl acetate and 0.1M hydrochloric acid. The organic phase was washed withsaturated sodium hydrogen carbonate solution followed by saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation the crude product was chromatographed on silica gel using 66% ethyl acetate in petroleum ether as eluent to obtain 44.69 g of diethyl (Z)-2-acetamido-2-(2-butenyl)malonate as a colourless oil;1H NMR (250 MHz, CDCl3) δ:1.2 (t, 6 H), 1.6 (d, 3 H), 2.0 (s, 3 H), 3.1 (d, 2 H), 4.2 (q, 4 H), 5.1(m, 1 H), 5.6 (m, 1 H), 6.7 (s, 1 H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:21])([CH3:20])[C:5]([N:7]1[CH2:19][CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:8]1)=[O:6].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([S:28]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]3[CH2:18][CH2:19][N:7]([C:5](=[O:6])[C:4]([CH3:21])([CH3:20])[CH3:3])[CH2:8][C:9]2=3)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)C(=O)N1CCc2c([nH]c3ccccc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCc2c(n(S(=O)(=O)c3ccccc3)c3ccccc23)C1
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
To a well-agitated suspension of sodium hydroxide (0.81 g, 20.2 mmol) in methylene chloride (10 mL) is added 2,2-dimethyl-1-(1,3,4,9-tetrahydro-pyrido[3,4-b]indol-2-yl)-propan-1-one (2.3 g, 8.98 mmol). The reaction mixture is stirred for 15 min, and then benzenesulfonyl chloride (1.89 g, 10.7 mmol) is added. The solution is stirred at room temperature for 1 h. The reaction is diluted with methylene chloride, washed with water then a saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) provides 2.0 g (56.2%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=[O:22].C(N(C(C)C)CC)(C)C.O>C(OC(=O)C)(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[C:21]([OH:23])=[O:22]
Reactant: COc1ccccc1CC(=O)O
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(=Cc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
25 g of 2-nitrobenzaldehyde, 28 g of 2-methoxyphenylacetic acid and 0.16 mol of diisopropylethylamine are boiled under reflux in 90 ml of acetic anhydride under nitrogen for 8 hours. After cooling to 60° C. , the mixture is poured onto 200 ml of hot water. The mixture is stirred for a further 2 hours, while cooling, and the product is filtered off with suction and washed with a little cold ethanol. Recrystallization from ethanol gives 38.7 g of the title compound of melting point 217°-219° C.
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]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[OH:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: OC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (1.2 g, 3.77 mmol) from experimental (1f) in 200 mL of CH2Cl2 was added Dess-Martin Periodinane (2.0 g, 4.71 mmol) portionwise. After 12 h, the reaction was quenched with 1M NaOH and extracted with 3×CH2Cl2. The CH2Cl2 extracts were dried over MgSO4, filtered, and concentrated by rotary evaporator to give (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanone in 100% yield. MS found: (M+H)+=317.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27](O)=[O:28])[CH:21]=[CH:20]3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].Cl.[CH2:35]([O:37][C:38](=[O:42])[CH2:39][NH:40][CH3:41])[CH3:36].Cl>CN(C1C=CN=CC=1)C.O>[CH2:35]([O:37][C:38](=[O:42])[CH2:39][NH:40][CH2:41][C:27]([C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:31])[C:2]([CH3:33])([CH3:32])[CH3:1])=[C:7]([CH3:30])[CH:8]=3)([CH2:13][CH3:14])[CH2:15][CH3:16])[CH:18]=2)[CH:23]=1)=[O:28])[CH3:36]
Reactant: CCOC(=O)CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)ccc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Product: CCOC(=O)CNCC(=O)c1ccc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
Dissolve 6-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carboxylic acid (0.10 g, 0.222 mmol), sarcosine ethyl ester HCl (0.069 g, 0.45 mmol), DMAP (0.108 g, 0.89 mmol) and EEDC (0.086 g, 0.45 mmol) in CH2CL2 (2 mL). Stir the mixture at RT for 16 h. Dilute the reaction mixture with CH2CL2 and water. Acidify to pH 1 using 1N HCl. Separate and discard the aqueous layer. Wash the organic layer with brine, dry over Na2SO4, and filter. Concentrate the filtrate and purify by silica gel radial chromatography (25:75 EtOAc:hex to 50:50 EtoAc:hex) to give the title compound as a white solid (0.093 g, 78%). MS (ES) m/e 546 (M+1).
Reaction SMILES: N[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[BrH:13].N([O-])=O.[Na+]>O.[Cu]Br>[Br:13][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1cc(-c2ccccc2)[nH]n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
20 g of 3-amino-5-phenylpyrazole were suspended in 200 ml of a 24% aqueous hydrogen bromide solution and a solution of 9.5 g of sodium nitrite in 20 ml of water was added dropwise at 0° C. in the course of 10 min. The mixture was stirred at 0° C. for 10 min. Then the obtained suspension was added in portions to a suspension of 19.8 g of copper(I) bromide in 100 ml of a 24% aqueous hydrogen bromide solution. Subsequently, the mixture was stirred at room temperature for 2 h and then extracted three times with 300 ml each of EA. The combined organic phases were washed twice with 100 ml each of water and once with 100 ml of a saturated aqueous sodium carbonate solution. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography on silica gel with EA/HEP (1:5) yielded 5.7 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH:4](O)[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:34]1[CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:35]1=[S:41]>CC(C)=O.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH:4]1[S:41][C:35]2=[N:34][CH2:40][CH2:39][CH2:38][CH2:37][N:36]2[C:5]1([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[OH:16]
Reactant: S=C1NCCCCN1
Reactant: COc1ccc(C(=O)C(O)c2ccccc2Cl)cc1OC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(C2(O)C(c3ccccc3Cl)SC3=NCCCCN32)cc1OC

Procedure:
A 6.13 g. portion of 2'-chloro-3,4-dimethoxybenzoin, 5.6 ml. of triethylamine and 20 ml. of toluene are mixed and stirred. A mixture of 1.55 ml. of methanesulfonyl chloride in 40 ml. of toluene is added over a period of one hour. A 50 ml. portion of water and more toluene are added. The organic layer is separated, washed with water and concentrated in vacuo to give 8.3 g. of 2'-chloro-3,4-dimethoxybenzoin methanesulfonate ester as a viscous oil. A mixture of this oil in 30 ml. of acetone is added to a stirred mixture of 1.95 g. of hexahydro-2H-1,3-diazepine-2-Thione in 150 ml. of acetone. The resulting mixture is stirred for 3 hours, then 3 hours at 45°-50° C., concentrated to 1/3 of its original volume and ether is added producing a gum. The mixture is concentrated free of solvents, 100 ml. of water and 2 ml. of ammonium hydroxide are added and the solid is filtered and washed with water. This solid is dissolved in 20 ml. of ethanol and refrigerated giving 1.3 g. of the desired product, m.p. 98°-100° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].Cl>C1COCC1>[OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]
Reactant: COCOc1ccc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)cc1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1c(O)c2c(-c3ccc(O)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To solution of 4-hydroxy-3-[4-(methoxymethoxy)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.1 g, 0.3 mmol) in THF (10 mL) was added 1N HCl (20 mL) and stirred at room temperature for 24 hours. The reaction mixture was then concentrated and purified on a RP-HPLC system to give the title compound. MS (ESI) m/e 282.9 (M−H)+; 1H NMR (500 MHz, DMSO-d6): δ ppm 12.53 (br s, 1H), 9.43 (br s, 1H), 7.21 (d, J=8.73, 2H,), 6.88 (s, 1H), 6.73 (d, J=8.42, 2H).
Reaction SMILES: [OH:1]O.[CH2:3]([S:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][CH:10]=1)=[O:8])[CH3:4]>C(O)(=O)C>[CH2:3]([S:5]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][CH:10]=1)=[O:8])=[O:1])[CH3:4]
Reactant: OO
Reactant: CCSCC(=O)c1ccc(-c2ccccc2F)cc1
Solvent: CC(=O)O
Product: CCS(=O)CC(=O)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.8 ml of 30% hydrogen peroxide were added dropwise, while stirring, to a suspension of 16.3 gm (59.5 millimols) of ethyl-[2-(2'-fluoro-4-biphenylyl)-2-oxo-ethyl]-sulfide in 170 ml of glacial acetic acid at 15° C. A clear solution was obtained which was stirred for 1 hour at room temperature. The reaction product was precipitated with water and recrystallized from isopropanol. Yield: 11.6 gm (67% of theory); m.p. 91-93° C.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([O:11]CC)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[N:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:20]([NH:2][C:3]2([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C1(N)CCCCC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Product: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Yield: 33.4 %

Procedure:
The same reaction procedure as used in Reference Example 4 was repeated by using 4.36 g (21 mmol) of ethyl 1-aminocyclohexanecarboxylate hydrochloride and 3.15 g (21 mmol) of morpholine carbonyl chloride, whereby 1.8 g of the captioned 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid was obtained in a yield of 33%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.O[CH2:22][CH2:23][O:24][C:25]1[CH:38]=[CH:37][C:36]2[C:27](=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:22][CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:36]3[C:27](=[CH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc2cc3ccccc3cc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3cc4ccccc4cc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(2-hydroxyethoxy)anthracene (1.26 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and the solids were filtered off, dissolved in dichloromethane, dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from dichloro-methane-diethyl ether provided 0.75 g of 4-[[2-(2anthracenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a yellow solid, mp 188°-189° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[N+]=[N-]>ClC1C=CC=CC=1Cl>[S:11]1[C:10]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH:1][C:14]=2[CH:13]=[CH:12]1
Reactant: [N-]=[N+]=Nc1ccccc1-c1cccs1
Solvent: Clc1ccccc1Cl
Product: c1ccc2c(c1)[nH]c1ccsc12
Temperature: 180 °C
Yield: 72.5 %

Procedure:
5.0 g of 2-(2′-azido-phenyl)-thiophene (B′) was dissolved in 100 ml of ortho-dichlorobenzene and the solution was refluxed at 180° C. for 12 hours. After the reaction was completed, the resulting solution was dried and purified by column chromatography using toluene. Finally, 3.12 g (yield: 77%) of 4H-thieno[3,2-b]indole (C′) was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[S:25])[NH:16]C(=O)C3C=CC=CC=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH2:16])=[S:25])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc(NC(=S)NC(=O)c3ccccc3)cc2)=NN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=S)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 81.1 %

Procedure:
To a suspension of 0.7 g of N-[[[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]amino]thioxomethyl]benzamide in 7 ml of ethanol is added 1.6 ml of 10% ethanolic sodium hydroxide followed by heating for two hours. The reaction mixture is cooled, diluted with water, and filtered to give 0.4 g of the product, N-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]thiourea mp 234°-235° C.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:14])[CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:14][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)N1CCc2c(N)cccc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCc2c(cccc2NS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 2-acetyl-5-amino-1,2,3,4-tetrahydroisoquinoline (6.6 g) in a mixture of dry pyridine (3 g) and dichloromethane (450 ml) at approximately 5° C. was added dropwise, over 15 minutes, benzenesulphonyl chloride (6.2 g). The orange solution was stirred overnight at room temperature and was then washed several times with water, dried and the solvent was then evaporated to give a dark orange oil. Crystallisation from 2-propanol gave 2-acetyl-5-phenylsulphonamido-1,2,3,4-tetrahydroisoquinoline as a pale pink solid (9.5 g) m.p. 131°-132° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C>O1CCOCC1>[CH2:10]([NH:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CNCc1ccccc1
Temperature: 90 °C
Yield: 77.6 %

Procedure:
A solution of diisopropylethylamine (155 g, 1.2 mol) and benzylamine (96 g, 0.9 mol) was added dropwise to a solution of ethyl bromoacetate (100 g, 0.6 mol) in dioxane (1000 mL). The resulting suspension was heated at about 90° C. for about 5 hours, and then was cooled to ambient temperature. Standard extractive workup with ethyl acetate afforded the title product as a yellow oil (90 g; yield=80%). LC-MS: m/z=194 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:10][CH:2]=[CH2:3])=[C:9]([O:12][CH2:9][CH:8]=[CH2:7])[C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([O:6][CH2:20][CH:21]=[CH2:22])=[O:5]
Reactant: C=CCBr
Reactant: O=C(O)c1cc(Cl)c(O)c(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(Cl)c(OCC=C)c(OCC=C)c1Cl
Reaction time: 8 h

Procedure:
2,5-Dichloro-3,4-dihydroxybenzoic acid (10.7 g, see J. Antibiotics, 1987, 40, 22) and K2CO3 (33.1 g) were suspended in DMF (150 ml), and treated with allyl bromide (14.7 ml). After stirring overnight, the mixture was filtered, diluted with ethyl acetate, washed with sodium bicarbonate, dried (MgSO4), filtered and evaporated to give allyl 2,5-dichloro-3,4-diallyloxybenzoate (14.7 g): NMR (CDCl3) 4.55-4.65 (m, 4H); 4.82 (m, 2H); 5.24-5.50 (m, 6H); 5.94-6.22 (m, 3H); 7.70 (s, 1H).
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH3:17])[C:7]=1[CH:18]=O.[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>>[CH3:17][C:8]1[C:7]2[CH:18]=[C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:26])[O:5][C:6]=2[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=1
Reactant: Cc1nn(-c2ccccc2)c(O)c1C=O
Reactant: CCOC(=O)CBr
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C)nn(-c3ccccc3)c2o1

Procedure:
Furo[2,3-c]pyrazole compounds were first synthesized by two of the present inventors, L. J. Haung and S. C. Kuo, and H. T. Li in an article published in J. Taiwan Pharm. Assoc. 31 (1), 47-55 (1979). Ethyl 3-methyl-1-phenylfuro[2,3-c]pyrazole-5-carboxylate (3) was synthesized in this article. As shown in the following Scheme 1, chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde (1) and ethylglycolate (2) were condensed to form ethyl 3-methyl-1-phenylfuro[2,3-c]pyrazole-5-carboxylate (3); or 5-hydroxy-3-methyl-1-phenylpyrazole-4-carboxal-dehyde acetate (4) was reacted with ethylbromoacetate (5) to obtain the ethyl 3-methyl-1-phenylfuro[2,3-c]pyrazole-5-carboxylate (3). The product produced by these two methods are very low in yield and stability. Therefore, only one furo[2,3-c]pyrazole compound (3) was synthesized and no further investigation was conducted in the above-mentioned article. ##STR1##