Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(O)(C)C.[NH2:6][C:7]([NH2:9])=[S:8].[CH3:10][N:11]([CH2:13][C:14]1[S:18][C:17]([CH2:19]O)=[CH:16][C:15]=1[CH3:21])[CH3:12]>>[ClH:1].[ClH:1].[C:7]([S:8][CH2:19][C:17]1[S:18][C:14]([CH2:13][N:11]([CH3:12])[CH3:10])=[C:15]([CH3:21])[CH:16]=1)(=[NH:9])[NH2:6]
Reactant: NC(N)=S
Reactant: Cc1cc(CO)sc1CN(C)C
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(CSC(=N)N)sc1CN(C)C
Yield: 82 %

Procedure:
In 35 ml of 21% (by weight) hydrochloric acid-isopropanol solution was suspended 2.1 g of thiourea, and 5 g of 5-(dimethylamino)methyl-4-methyl-2-thenyl alcohol was added thereto, after which the resulting mixture was subjected to reaction under reflux for 15 hours. After the mixture was allowed to stand at room temperature, the crystals deposited were collected by filtration to obtain 7 g (yield 82%) of 2-amidinothiomethyl-5-(dimethylamino)methyl-4-methylthiophene dihydrochloride having a melting point of 212°-214° C. (decomp.). NMR (d6 -DMSO) δ values: 2.31 (3H, s, --CH3), 2.82 (6H, s, --CH3 ×2), 4.58 (2H, s, >CH2), 5.04 (2H, s, >CH2), 7.16 (1H, s, thiophene ring H), 9.76 (4H, bs, ##STR224## 11.01 (1H, bs, HCl)
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][N:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Nc1nccnc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A suspension of 3-aminopyrazine methanol, 6.3 g (0.05 mol) and manganese dioxide (38.0 g) in 400 mL of chloroform is stirred at room temperature for two hours and the resulting solid is filtered off. The filtrate is evaporated to dryness which gives the desired product as a yellow crystalline solid, (5.00g, 82% yield) having a melting point 110°-114° C.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17]3)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:24]=[C:25]1[C:30]2=[CH:31][NH:32][C:33]([CH:34]=O)=[C:29]2[CH2:28][CH2:27][O:26]1>>[N:1]1([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[C:17]3=[CH:34][C:33]2[NH:32][CH:31]=[C:30]3[C:25](=[O:24])[O:26][CH2:27][CH2:28][C:29]=23)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCCc4ccccc43)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-(3,4-Dihydro-2H-quinoline-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3([CH2:26][O:25][C:24]4[CH:27]=[C:28]5[C:32](=[CH:33][C:23]3=4)[CH2:31][CH2:30][O:29]5)[C:15]2=[O:34])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3([CH2:26][O:25][C:24]4[CH:27]=[C:28]5[C:32](=[CH:33][C:23]3=4)[CH2:31][CH2:30][O:29]5)[C:15]2=[O:34])=[CH:35][CH:36]=1
Reactant: O=C1N(Cc2ccc(OCc3ccccc3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1N(Cc2ccc(O)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A mixture of 1′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one (2.4 g, 5.1 mmol) and palladium on carbon (10% w/w, 0.49 g) in anhydrous methanol (10 mL) and ethyl acetate (50 mL) was hydrogenated at ambient temperature under a balloon pressure for 16 h. The mixture was filtered through a pad of diatomaceous earth The pad was washed with ethyl acetate (50 mL) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with a 25% to 50% gradient of ethyl acetate in hexanes to afford 1′-(4-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (1.86 g, 94%) as a colorless solid: mp 226-227° C.; 1H NMR (300 MHz, CDCl3) δ 7.25-7.13 (m, 4H), 7.06-6.99 (m, 1H), 6.87-6.82 (m, 1H), 6.78-6.72 (m, 2H), 6.44-6.41 (m, 2H), 5.27 (s, 1H), 4.88 (ABq, J=69.0, 15.3 Hz, 2H), 4.84 (ABq, J=82.9, 9.0 Hz, 2H), 4.55-4.46 (m, 2H), 2.96-2.86 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.2, 161.8, 161.3, 155.5, 142.1, 132.8, 128.8, 128.7, 127.5, 123.9, 123.5, 120.0, 119.9, 118.8, 115.8, 109.4, 93.3, 80.5, 72.4, 70.0, 57.8, 43.7, 28.9; MS (ES+) m/z 385.9 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][C@@H:6]([CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH:7][C:8](=[O:33])[CH2:9][N:10]([C:14](=[O:32])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]=1[NH2:31])[CH:11]1[CH2:13][CH2:12]1)C.[OH-].[Na+]>CCO.CCOC(C)=O>[C:24]([C:20]1[C:19]([NH2:31])=[C:18]([CH2:17][CH2:16][CH2:15][C:14]([N:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][C:8]([NH:7][C@H:6]([CH2:34][CH2:35][C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)[CH2:5][C:4]([OH:45])=[O:3])=[O:33])=[O:32])[CH:23]=[CH:22][N:21]=1)([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25]
Reactant: CCOC(=O)C[C@@H](CCc1c[nH]c2ccccc12)NC(=O)CN(C(=O)CCCc1ccnc(C(=O)OC(C)(C)C)c1N)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1nccc(CCCC(=O)N(CC(=O)N[C@H](CCc2c[nH]c3ccccc23)CC(=O)O)C2CC2)c1N

Procedure:
Ester 8-1 (223 mg, 0.36 mmol) was dissolved in 4 mL EtOH, then 1 N NaOH (0.90 mL, 0.90 mmol) was added. After a few hours the reaction was diluted with EtOAc, extracted with water and the pH of the aq. phase was adjusted to 1 with 10% KHSO4. The aqueous layer was extracted with EtOAc (2×), the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated, providing 8-2 as an oil.
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27]C(=O)OC(C)(C)C)=[CH:26][C:20]=4[S:19](=[O:36])(=[O:35])[N:18]=3)[C:7]2=[O:37])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:37])[N:6]([NH:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:36])(=[O:35])[C:20]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A slurry of the product of Example 464A (1.5 g, 2.85 mmol) in dichloromethane (10 mL) at 0° C. was treated dropwise with 6 mL of trifluoroacetic acid, stirred at 25° C. for 2 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 10% aqueous sodium bicarbonate (3×50 mL), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (1.1 g, 91% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=[O:15].[CH:16]1[C:21]([NH:22][NH2:23])=[CH:20][CH:19]=[C:18]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:17]=1.Cl>O>[O:15]=[C:2]1[C:3](=[N:23][NH:22][C:21]2[CH:20]=[CH:19][C:18]([S:24](=[O:26])(=[O:25])[NH2:27])=[CH:17][CH:16]=2)[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=2)[NH:1]1
Reactant: NS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(S(N)(=O)=O)cc32)cc1

Procedure:
The title compound was prepared from 1H-indole-2,3-dione-5-sulfonic acid amide and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 7.04 (d, J=8.4 Hz, 1H), 7.25 (s, 2H), 7.26 (s, 2H), 7.60 (d, J=8.9 Hz, 2H), 7.70 (dd, J=8.2, 1.9 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.98 (d, J=1.6 Hz, 1H), 11.43 (s, 1H), 12.75 (s, 1H); APCI−MS m/z 395 (M)−+. Anal. Calcd for C14H13N5O5S2.0.5 H2O: C, 41.58; H, 3.49; N, 17.32; S, 15.86. Found: C, 41.67; H, 3.46; N, 17.26; S, 15.78.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:10]([O-])=[O:11].[Na+].[Cl-].[K+]>C(O)(=O)C.O>[OH:11][N:10]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(C)=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Under N2, a solution of ethyl acetoacetate (286 mL, 292 g, 2.24 mol) dissolved in 300 mL of acetic acid was cooled to -10° C. Maintaining that temperature, NaNO2 (80 g, 2.61 mol) in 400 mL of water was slowly added, and the mixture then stirred 30 minutes at 0° C., at which time KCl (160 g, 2.15 mol) in 800 mL of water was added over 20 minutes, the mixture stirred for an additional 30 minutes at0° C. and then extracted 3×1 L ether. The organic layers were combined, washed 2×1 L water and 1×1L brine, dried (MgSO4) and stripped to yield 343.3 g (96%) of title product as an oil; tlc Rf 0.3 (1:19 CH3OH:CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH:23]1([C:29]2[O:30][C:31]([CH3:47])=[C:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[O:30][C:31]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (300 mg, 1.0 mmol), toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester (386 mg, 1.06 mmol) and Cs2CO3 (423 mg, 1.3 mmol) were combined in anhydrous DMF (7 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled, diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) to provide the ethyl ether compound as a colorless oil (177 mg, 28%).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[CH3:14].[C:15](=[O:17])=[O:16]>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:15]([OH:17])=[O:16])=[C:9]([F:13])[C:8]=1[CH3:14]
Reactant: Cc1c(F)cccc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(Cl)ccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
n-Butyllithium (2.5M in hexane, 100 ml) was added to a cooled solution of 2-chloro-6-fluorotoluene (36.1 g) in dry tetrahydrofuran while maintaining the temperature below -60° C. The mixture was stirred at -78° C. overnight then poured onto solid carbon dioxide pellets. The mixture was stirred and allowed to warm to room temperature. It was acidified to pH 1 and extracted with ether. The organic layer was extracted into aqueous sodium hydroxide solution (2M) and water. The combined aqueous extracts were acidified to pH 1 and the solid formed was filtered off and washed with water and n-hexane to give 4-chloro-2-fluoro-3-methylbenzoic acid (40.35 g) as a white solid, NMR (DMSO-d6) 2.3(d,3H), 7.4(d,1H) 7.7(t,1H).
Reaction SMILES: [NH2:1][CH:2]([P:6]([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O>[CH2:15]([O:14][C:12]([NH:1][CH:2]([P:6]([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C(N)P(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(NC(=O)OCc1ccccc1)P(O)O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1-(diphenylmethylamino)-2-methylpropylphosphonous acid (12 g) was suspended in 100 mL of 48% hydrobromic acid, then heated at 100° C. for 2 hours until two distinct phases separated. The mixture was evaporated to dryness in vacuo, and the residue taken up in 100 mL of water. The aqueous solution was washed several times with ether to remove diphenylmethyl bromide and then evaporated to give an 80 mL solution of 1-amino-2-methylpropylphosphonous acid, a compound of formula (Xd). The solution of 1-amino-2-methylpropylphosphonous acid in 80 ml water was adjusted to pH 9.5 using 4 N NaOH, and the solution was cooled to 0° C. by an ice bath. Benzyl chloroformate (7.1 mL, 47 mmol) was added dropwise over 30 minutes and the resulting mixture was stirred for an additional 12 hours while the pH was maintained at pH 9-9.5 by periodic addition of 4 N NaOH. The reaction mixture was washed with ether (3×100 mL) to remove excess benzyl chloroformate. The aqueous solution was acidified using concentrated HCl to pH 1, then extracted by ethyl acetate (4×100 mL). The organic phase was dried over Na2SO4 and concentrated to afford 9.2 g of 1-(benzyloxycarbonylamino)-2-methylpropylphosphonous acid, as a white solid, which could be used in further reactions without further purification.
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][O:16][CH2:17][CH2:18][O:19]C(=O)C2C=CC=CC=2)=C(Cl)N=1>C(O)(C)C>[OH:19][CH2:18][CH2:17][O:16][CH2:15][N:12]1[CH:11]=[N:10][C:9]2[C:2](=[S:3])[NH:1][C:6]([NH2:5])=[N:14][C:13]1=2
Reactant: NC(N)=S
Reactant: Nc1nc(Cl)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Solvent: CC(C)O
Product: Nc1nc2c(ncn2COCCO)c(=S)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
Thiourea (0.28g) was added to a refluxing solution of 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (1.27g) in isopropanol (40ml). The reaction mixture was heated at reflux for 11/2 hours and then chilled. 9-(2-benzoyloxyethoxymethyl)thioguanine (0.58g, m.p. 199°-202° C.) was removed by filtration. This was added to 40ml of aqueous ammonia (about 7N) and the mixture heated on a stream bath for 10 minutes and then stirred overnight at room temperature. The water and ammonia were removed in vacuo and the residue triturated with acetone and then with ether to remove benzamide. The remaining solid was recrystallized twice from water to give yellow flakes of 9-(2-hydroxyethoxymethyl)thioguanine (0.26g., m.p. 251°-254° C.).
Reaction SMILES: C(=O)([O-])[O-:2].[Na+:5].[Na+].[O-:7][Si:8]([O-:10])=[O:9].[Na+].[Na+]>>[Si:8]([O-:2])([O-:10])([O-:7])[O-:9].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=C([O-])[O-]
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
A crystalline alkali metal phyllosilicate, as described on page 2, was prepared by dissolving 810 g of anhydrous sodium carbonate in 60 kg of water glass having a percentage composition Na2O/SiO2/H2O=15.3/29.7/55. The solution was spray-dried in a laboratory spray drier (spray tower) from Anhydro to give an amorphous sodium silicate having an active substance content of 82%. 15 kg of the amorphous sodium silicate were heat-treated at 720° C. for 90 min in a muffle furnace (Nabertherm, model W1000/H). This was repeated once more. The cooled silicate powder (about 24 kg) was pulverized with a jaw crusher and a disk mill. 2.55 kg of the silicate powder were mixed with of Arbocell FIC 200 in a tumble mixer. The mixture was compacted in accordance with the general procedures “Roll compaction” at a pressure of 20 kN, and processed in accordance with the general procedure “Production of particle size fractions” to give a particle size fraction of from 500 to 1000 μm.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([OH:16])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:36])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[CH3:17][N:18]([CH3:36])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:34])[CH3:35])=[CH:29][CH:28]=2)[C:14]([CH:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])=[CH:23][CH:24]=1
Reactant: CC(C)c1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(C(C)C)cc32)cc1
Yield: 28.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.07 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-7-isopropyl-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was obtained. melting point: 123-125° C.
Reaction SMILES: [CH2:1]([C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C:20]([CH:21]=[C:22]([C:30]([O:32]C)=[O:31])[CH2:23][CH2:24]1)=[CH:19][CH2:18]3)=[O:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[CH2:1]([C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C:20]([CH:21]=[C:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24]1)=[CH:19][CH2:18]3)=[O:10])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1=CC2=CC[C@H]3[C@@H]4CC[C@H](C(=O)CCc5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CCc1ccccc1

Procedure:
A mixture of methyl 17β-(phenethylcarbonyl)-androsta-3,5-diene-3-carboxylate, K2CO3, water and methanol is heated at reflux for about 5 hours. Acidification followed by conventional workup yields title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O[CH:11]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[C:12]([OH:14])=[O:13].O>OS(O)(=O)=O>[C:16]([NH:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:12]([OH:14])=[O:13])(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C(NC(O)C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(NC(C(=O)O)c1ccc2c(c1)CCO2)c1ccccc1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
2,3-Dihydrobenzofuran (4.8 g, 40 mmole) is stirred with 9.0 g (40 mmole) of α-hydroxy-hippuric acid in 200 ml of 10% H2SO4 -90% acetic acid mixture. The reaction is run at room temperature for 0.5 hour. After the half-hour, the reaction mixture is poured into 500 ml of water. The aqueous solution is extracted with ethyl acetate (4×100 ml). The ethyl acetate extracts are dried over magnesium sulfate and then evaporated to give α-benzamido(2,3-dihydro-5-benzofuranyl)acetic acid. Recrystallization of the crude benzamido compound from hexanemethylene chloride gives 11.56 g (94% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:25](=[O:26])[CH2:24][Cl:23])[C@@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (795 mg, 3.68 mmol) in DCM (20 mL) was added triethylamine (1.53 mL, 11.04 mmol). The resulting mixture was cooled to 0° C. before the dropwise addition of chloroacetyl chloride (325 μL, 4.05 mmol). The mixture was warmed to RT and stirred for 5 h. The reaction mixture was partitioned between a saturated aqueous solution of NaHCO3 and DCM. The organic layer was separated and the aqueous layer extracted with DCM. The combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as a colourless oil which was a mixture of rotamers (710 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([NH:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[O:20])[CH2:14][CH:13]2[C:30]([O:32]CC)=[O:31])=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>CC(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([NH:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[O:20])[CH2:14][CH:13]2[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(CC(=O)Nc2c(Cl)cccc2Cl)CCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(=O)O)C1)Nc1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 3.3 parts of ethyl 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-[(2,6-dichlorophenyl)amino]-2-oxoethyl]-2-piperazinecarboxylate and 60 parts of a hydrochloric acid solution 12N was stirred for 8 hours at 100° C. in an oil-bath. 2-Propanone was added whereupon a solution was obtained. The pH was adjusted to 5 with sodium hydrogen carbonate and the 2-propanone was evaporated: a sticky oil in water was remained. The aqueous phase was decanted and the sticky oil was taken up in 24 parts of 4-methyl-2-pentanone while warming. The solid product was filtered off and boiled in 120 parts of acetonitrile. After cooling for a while, the less pure product was filtered off and the filtrate was cooled. The product was filtered off and dried, yielding 0.31 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-[(2,6-dichlorophenyl)amino]-2-oxoethyl]-2-piperazinecarboxylic acid; mp. 204.3° C. (compound 172).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]([OH:18])=O)[C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH:10]3[C:11]([C:12]=2[CH:13]=1)=[N:26][N:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](=[O:18])[CH2:15]3)([O-:3])=[O:2]
Reactant: O=C(O)CC1CCc2ccc([N+](=O)[O-])cc2C1=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=C1CC2CCc3ccc([N+](=O)[O-])cc3C2=NN1c1ccccc1

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid and phenylhydrazine in ethanol is refluxed under heating for 10 hours. The ethanol is distilled off and to the residue is added acetic acid and then the resulting mixture is refluxed under heating for 8 hours. After the acetic acid is distilled off, the mixture is extracted with chloroform and the extract is washed with water. After drying over magnesium sulfate anhydride, the chloroform is distilled off to give 9-nitro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.