Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>O>[C:1]([NH:4][C:5]1[C:13]([N+:15]([O-:17])=[O:16])=[C:9]([C:8]([Br:14])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CC(=O)Nc1ccc(Br)c(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
5-(Acetylamino)-2-bromobenzoic acid (5.00 g, 19.4 mmol) was gradually added to fuming nitric acid (10 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to give the title compound (2.19 g, yield 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:17]C(C)C)[C:11]=2[O:10][CH:9]=1)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([OH:17])[C:11]=2[O:10][CH:9]=1)=[O:7]
Reactant: COc1cc(C(=O)c2coc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(=O)c2coc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzofuran (23 mg, 0.058 mmol, co-distilled with toluene before use) in dry dichloromethane (1 mL) was treated with solid aluminium chloride (16 mg, 0.116 mmol). The reaction mixture was stirred for 20 minutes at room temperature (tlc) then quenched with saturated ammonium chloride solution and extracted with ethyl acetate (10 mL). The organic layer was washed with water (5 mL), dried over magnesium sulphate and concentrated under vacuum. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/ethyl acetate; 80:19:1) to afford the title compound as a creamy white crystalline solid; (18 mg, 86%); 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H, C2H), 7.63 (d, 1H, J=8.53 Hz), 7.14 (s, 2H, benzoyl Hs), 7.02 (d, 1H, J=8.38 Hz), 3.97 (s, 3H, OMe), 3.93 (s, 3H, OMe), 3.89 (s, 6H, 2×OMe); 13C NMR (75 MHz, CDCl3) δ 188.73 (CO), 152.82, 151.24, 144.54, 143.30, 141.76, 133.97, 130.87, 120.92, 120.62, 112.43, 109.16, 106.06, 60.62, 56.85, 55.97.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1)=O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:35]=[CH:34][C:32]([NH:33][CH2:1][C:3]3[CH:12]=[C:11]4[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]4)=[CH:5][CH:4]=3)=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: N#Cc1ccc2ccc(C=O)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-Formyl-2-naphthalenecarbonitrile obtained in Reference Example 1 (849 mg) and 1,370 mg of 4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]aniline were dissolved in 10 ml of dichloromethane and 2.7 ml of acetic acid, 1,290 mg of sodium triacetoxyborohydride was added to the solution, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was washed with 2M potassium carbonate, water and 10% citric acid aqueous solution in that order, dried over sodium sulfate, and then evaporated. By recrystallizing the resulting residue from methanol, 1,698 mg of 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14].[Li]CCCC.O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of 5-fluoro-1H-indole (2.5 g, 18.52 mmol) and chlorotriisopropyl-silane (3.92 g, 20.4 mmol) in anhydrous THF (75 mL) at −78° C. was added dropwise a solution of n-BuLi in THF (1.6 mol/L, 12.7 mL, 20.37 mmol) at a rate to maintain the internal reaction temperature below −70° C. After the addition was completed, the mixture was stirred at −78° C. for 1 h and then poured into water (250 mL), extracted with DCM (100 mL×3), and concentrated in vacuo to afford 5-fluoro-1-(triisopropylsilyl)-1H-indole as a yellow oil (5.27 g, 97.6%). MS (ESI): m/z=292.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[CH:12]([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:11]([CH:12]([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C(CC(=O)C(F)F)c1nc2ccc(Cl)cc2s1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3ccc(Cl)cc3s2)cc1

Procedure:
The procedure of Example 9 was repeated using 1-(6-chlorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(6-chlorobenzothiazol-2-yl)-3-difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide. NMR(DMSO-d6) δ: 7.23 (1H, t, J=54.1 Hz), 7.56 (2H, bs), 7.57 (1H , s), 7.56-7.60 (1H, m), 7.76-7.80 (2H, m), 7.93-7.97 (3H, m), 8.36 (1H, d, J=2.3 Hz); mp 242-244° C. (toluene)
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11]>>[N+:10]([CH:13]=[CH:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1)([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Product: O=[N+]([O-])C=Cc1ccccc1

Procedure:
In the present application, the Henry reaction between p-hydroxy benzaldehyde and nitromethane at 90° C. was carried out, resulting in the formation of nitrostyrene. Typically, 20 mg of a particular aminofunctionalized mesoporous sample was added into a mixture of 122 mg (1 mmol) p-hydroxybenzaldehyde and 10 mL of nitromethane. The reaction mixture was stirred at 90° C. under nitrogen and aliquots of the reaction product were taken with a filter syringe and characterized by solution 1H NMR spectroscopy and GC-MS over the course of the reactions. The percent yield and conversion were determined by using 1H NMR spectra measured in deutrated acetone.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:30])[CH:21]=2)[C:11]1=[O:31].Cl>O1CCOCC1.O>[CH3:30][N:22]1[C:23]2[C:28](=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:32])=[O:2])[C:11]2=[O:31])=[CH:21]1
Reactant: COC(=O)c1ccccc1-n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2c1c(Cn1c(=O)n(-c3ccccc3C(=O)O)c3ccccc31)cn2C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 2-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-benzoic acid methyl ester (45 mg, 0.11 mmol) in 1,4-dioxane (1.0 mL) is added LiOH monohydrate (5.6 mg, 0.13 mmol) in water (0.1 mL) at room temperature. The solution is stirred at the same temperature for 16 hours. Then another 1.0 mg of LiOH monohydrate is added and the reaction is continued for another 2 hr. Then 0.5 mL of 1.0 M HCl is added along with 10 mL of water. The mixture is extracted with EtOAc (3×15 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC affords 41 mg (95%) of 2-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-benzoic acid. LCMS (ESMS): m/z 412.17 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O>[CH2:12]([O:19][C:20]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To the solution of piperidine-3-carboxylic acid (1.3 g, 10 mmol) in water (20 mL) was added sodium hydroxide (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.2 g of solid of 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid was obtained. LC-MS (ESI) m/z: 264 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13]O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>[Pd].CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CO)Cc1ccc(C(C)(C)C)cc1
Reactant: C1CCNCC1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1
Yield: 94 %

Procedure:
A mixture of 153 parts of 3-p-tertiary butylphenyl-2-methyl-propanol, 70 parts of piperidine, 230 parts of methanol and 20 parts of catalyst, comprising 0.5% by weight of Pd and 5% by weight of Nd2O3 on Al2O3, is hydrogenated in a stirred autoclave of 1,000 parts by volume capacity, at 70° C. under a hydrogen pressure of 50 bar, until the pressure remains constant. The autoclave is then allowed to cool, the catalyst is filtered off and the filtrate is purified by distillation. 195 parts of N-(3'-(p-tertiary butylphenyl)-2'-methylpropyl)-piperidine, boiling point 117° C./0.2 mm Hg, are obtained. The yield is 94% of theory.
Reaction SMILES: OC1C(C(F)(F)F)=C(OCC2C=CC(OC3C=CC=C(C4[N:28]=[N:29][NH:30]N=4)C=3)=CC=2)C=CC=1C(=O)C.[C:35]([C:38]1[CH:60]=[CH:59][C:41]([O:42][CH2:43][C:44]2[CH:58]=[CH:57][C:47]([CH2:48][C:49]3[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=3)[C:52]#[N:53])=[CH:46][CH:45]=2)=[C:40]([C:61]([F:64])([F:63])[F:62])[C:39]=1[OH:65])(=[O:37])[CH3:36]>>[OH:65][C:39]1[C:40]([C:61]([F:63])([F:64])[F:62])=[C:41]([O:42][CH2:43][C:44]2[CH:58]=[CH:57][C:47]([CH2:48][C:49]3[CH:56]=[CH:55][CH:54]=[C:51]([C:52]4[N:28]=[N:29][NH:30][N:53]=4)[CH:50]=3)=[CH:46][CH:45]=2)[CH:59]=[CH:60][C:38]=1[C:35](=[O:37])[CH3:36]
Reactant: CC(=O)c1ccc(OCc2ccc(Cc3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Reactant: CC(=O)c1ccc(OCc2ccc(Oc3cccc(-c4nn[nH]n4)c3)cc2)c(C(F)(F)F)c1O
Product: CC(=O)c1ccc(OCc2ccc(Cc3cccc(-c4nn[nH]n4)c3)cc2)c(C(F)(F)F)c1O

Procedure:
The title compound is prepared essentially as described for 1-(2-hydroxy-4-{4-[3-(2H-tetrazol-5-yl)-phenoxy]-benzyloxy}-3-trifluoromethyl-phenyl)-ethanone employing 3-[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-benzyl]-benzonitrile (58%). LC-MS (m/e): 467 (M−1); 1H NMR (DMSO-d6) δ 13.79 (1 H, s), 8.21 (1H, d), 7.80-8.00 (2H, m), 7.30-7.60 (6H, m), 6.92 (1H, d), 5.35 (2H, s), 4.08 (2 H, s), 2.65 (3H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:11]2([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:16][CH2:17]1
Reactant: [H][H]
Reactant: CN1CCN(C2(C)CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C2(C)CCNCC2)CC1
Reaction time: 22 h

Procedure:
A suspension of 0.99 g (3.27 mmol) 1-(1-benzyl-4-methyl-piperidin-4-yl)-4-methyl-piperazine and 200 mg 10% Pd/C in 25 mL MeOH was hydrogenated at 50° C. and 50 psi hydrogen pressure for 2 h. To complete the reaction a further 200 mg catalyst were added and the reaction mixture was hydrogenated for a further 22 h at 60° C. and 50 psi hydrogen pressure. The catalyst was filtered off and the filtrate evaporated to dryness. The product was reacted further without purification.
Reaction SMILES: [C:1]([N:3]([CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:4](=[NH:7])SC)#[N:2].[CH3:22][NH2:23]>C(O)C>[C:1]([N:3]([CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:4]([NH:23][CH3:22])=[NH:7])#[N:2]
Reactant: CSC(=N)N(C#N)C(c1ccccn1)c1ccccc1C
Reactant: CN
Solvent: CCO
Product: CNC(=N)N(C#N)C(c1ccccn1)c1ccccc1C
Yield: 85 %

Procedure:
A mixture consisting of 5.9 g (0.02 mol) of N-cyano-S-methyl-N-[α-(2-pyridyl)orthomethylbenzyl]isothiourea prepared in (a), 30 ml of 20% solution of methylamine in ethanol and 70 ml of ethanol was prepared and reacted at room temperature overnight. The reaction solution was concentrated under a reduced pressure. The residue was recrystallized from ethyl acetate to produce 4.7 g of the subject material, N-cyano-N'-methyl-N-[α-(2-pyridyl)orthomethylbenzyl]guanidine (yield: 85.0%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2.[Si]([O:33][CH2:34][CH:35]=O)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH:24][CH2:35][CH2:34][OH:33])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC1(C)CCCc2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCCc2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 60 mg (0.16 mmol) of 1-[4-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 34 μl (0.16 mmol) of (tert-butyldimethylsilanyloxy)acetaldehyde. The protecting group is cleaved off using a 4N HCl solution in dioxane. The purification is carried out by means of preparative HPLC. The product is in the form of the formate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>C(O)CCC>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16]
Reactant: COc1ccnc(Cl)n1
Reactant: O=C(c1ccco1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1ccnc(N2CCN(C(=O)c3ccco3)CC2)n1
Yield: 70.2 %

Procedure:
A solution of 1.0 g (6.92 mmol) of 2-chloro-4-methoxypyrimidine, 1.49 g (8,30 mmol) of 1-(2-furylcarbonyl)piperazine and 1.39 g (13.84 mmol) of triethylamine in 20 mL of n-butanol is maintained under gentle reflux conditions overnight. The solvent is evaporated off under reduced pressure and the crude residue is diluted in chloroform and washed in water. The organic phase is dried over NaSO4 and evaporated to dryness to give a crude product which is purified using silica-gel chromatography eluting with ethyl acetate/petroleum ether 70:30 to yield an oil which solidifies when left to stand. The solid is suspended in petroleum ether to yield 1.4 g (4.86 mmol) of 2-[4-(2-furylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine. m.p.=85-86° C.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([C:23]([O:25]C)=[O:24])[N:20]([CH3:22])[CH:21]=2)=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCOCC1>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([C:23]([OH:25])=[O:24])[N:20]([CH3:22])[CH:21]=2)=[CH:15][CH:16]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 0.5 M solution of NaOH (2.0 eq) was added to a solution of 5 (1.0 g, 3.027 mmol) in dioxane (40 mL). The reaction mixture was allowed to stir at room temperature for 6 hours at which point TLC revealed completion of reaction. Excess 1,4-dioxane was evaporated under vacuum and the residue was diluted with water. The resulting solution was acidified with 0.5 M HCl. The product was extracted from water with 2× ethyl acetate (100 mL×2) and the organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The product was purified using flash chromatography (ethyl acetate/n-hexane 2:8). Yield—0.92 g, 96.8%. IR (FTIR, vmax/cm−1): 3371, 2979, 1698, 1671, 1522, 1445, 1367, 1285, 1161, 1112, 1047, 823, 803, 762, 714, 631; 1H-NMR (400 MHz, CDCl3): δ 8.33 (1H, s), 7.55 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 7.36 (d, 1H, J=2.0 Hz), 7.22 (d, 1H, J=2.0), 3.97 (s, 3H), 1.50 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 162.3, 153.7, 138.6, 123.0, 127.1, 126.0, 124.4, 124.0, 119.5, 115.1, 79.9, 36.9, 28.6; EIMS m/z (+EI) calc. for C17H20N2O4 (M)+ 316.35. found 315.16 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].O[N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1.C(Cl)(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33]([O:35][N:37]4[C:41](=[O:42])[CH2:40][CH2:39][C:38]4=[O:43])=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)ON5C(=O)CCC5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
To a solution of N-(cholest-5-en-3β-oxycarbonyl)glycine (2.92 g) in a mixture of dioxane (40 ml) and chloroform (6 ml) were added successively N-hydroxysuccinimide (0.69 g) and dicyclohexylcarbodiimide (1.236 g) at 0° C. and the reaction mixture was stood for 16 hours in a refrigerator. The resulting precipitate was collected by filtration and the filtrate was concentrated in vacuo to give succinimidyl N-(cholest5-en-3β-oxycarbonyl)glycinate (3.23 g).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[NH:23]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][CH2:32][CH2:33][N:23]1[C:14]([C:12]1[O:13][C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)=[O:16])=[O:26])[CH3:29]
Reactant: CCOC(=O)C1CCCCN1
Reactant: O=C(O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCN1C(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Yield: 59.4 %

Procedure:
A solution of 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (of Intermediate 8; 0.098 g, 0.33 mmol), ethyl pipecolinate (Aldrich; 0.139 g, 0.88 mmol), 1-ethyl-3-(3-dimethylaminopropyl) hydrochloride (Avocado; 0.13 g, 0.68 mmol), and N,N-dimethylaminopyridine (0.083 g, 0.68 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The solvents were evaporated under reduced pressure, and water and ethyl acetate were added. The aqueous phase was extracted three times with ethyl acetate, and the combined organic layers were dried (sodium sulfate), filtered, evaporated, and purified using a Biotage Flash 40 purification system, eluting with methylene chloride/acetone 9:1, to give (rac)-1-[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-piperidine-2-carboxylic acid ethyl ester as a colorless oil (0.085 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)=[CH:14][C:13]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Cl)c(Oc2ccccc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(Oc2ccccc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-phenoxybenzaldehyde in an analogous manner to that described in Example 1 gave 9-(4-chloro-3-phenoxyphenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a yellow crystalline solid of melting point 246-248° C.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([C:56](=[NH:72])[N:57](C)[C:58](OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:52][CH2:51]2)=[O:49])[CH2:43]1>>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([OH:23])=[O:22])=[C:16]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:55][CH2:54][N:53]([C:56](=[NH:72])[NH:57][CH3:58])[CH2:52][CH2:51]4)=[O:49])[CH2:43]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: CN(C(=N)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: CNC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)CC1

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-1-methyl-2-[4-(methyl-4-nitrobenzyloxycarbonylamidino)piperazin-1-yl-carbonyl]pyrrolidine (prepared as described in Preparation 105) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.