Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.[CH:18]1([C:21]2[C:22]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[C:22]([N:30]3[CH2:31][CH2:32][N:33]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[CH3:16])=[O:13])[CH2:34][CH2:35]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:19][CH2:20]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 28.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (255 mg) described in Preparation Example 29 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (243 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Example 87, the title compound (137 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH:12]=[C:11]([O:19][CH3:20])[C:10]=2[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[C:21](Cl)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Cl-].[Cl-].[Cl-].[Al+3].CCCCCC>ClCCl>[CH3:20][O:19][C:11]1[C:10]2[C:6]3[S:7][C:8]([C:21](=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:9][C:5]=3[CH:4]=[C:3]([O:2][CH3:1])[C:18]=2[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1
Reactant: COc1cc2ccsc2c2c(OC)cc3ccsc3c12
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCCCCCCC(=O)c1cc2cc(OC)c3c4sccc4cc(OC)c3c2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
4,9-Dimethoxynaphtho[1,2-b:5,6-b′]dithiophene (0.90 g, 3.0 mmol) was solubilized in anhydrous dichloromethane (20 mL). Dodecanoyl chloride (0.765 g, 3.5 mmol) was then added and stirring was continued for 10 minutes at this temperature. Aluminum trichloride (0.465 g, 3.5 mmol) was then added in 3 portions. The mixture was stirred overnight at room temperature. The mixture was cooled in ice water and extracted with chloroform (200 mL) and washed with water (100 mL) and brine (50 mL). After the solvent was removed, the residual was purified using a silica column with dichloromethane:hexane (1/3) to give compound 1-(4,9-dimethoxynaphtho[1,2-b:5,6-b′]dithiophen-2-yl)dodecan-1-one as a pale yellow solid (0.78 g, ˜54% yield). 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.50 (m, 2H), 7.42 (s, 1H), 4.24 (s, 3H), 4.22 (s, 3H) 3.07. (t, J=7.0 Hz, 2H), 1.83 (m, 2H), 1.39 (m, 18H); 0.88 (m, J=6.0 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[CH3:13].[CH2:16]([C:18]1[S:22][C:21]([C:23](=[O:25])[CH3:24])=[CH:20][C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:17]>C(O)C.Cl.C(O)(C)C>[OH:1][CH:2]([CH2:14][OH:15])[CH2:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH2:8][CH2:24][C:23]([C:21]2[S:22][C:18]([CH2:16][CH3:17])=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[O:25])=[CH:6][C:5]=1[CH3:13]
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1CC(O)CO
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: CCc1sc(C(=O)CCc2cc(C)c(CC(O)CO)c(C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
A solution of 4-(2,3-dihydroxy-propyl)-3,5-dimethyl-benzaldehyde (64 mg, 0.308 mmol) and 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (50 mg, 0.218 mmol) in ethanol (2 mL) and 5 N HCl in isopropanol (0.5 mL) is stirred at rt for 5 days. The solvent is removed in vacuo and the residue is separated by prep. HPLC. Product containing fractions are treated with sat. aq. NaHCO3 and 3 M aq. NaOH (5 mL). The mixture is stirred at rt for 1 h, then extracted with DCM. The solvent of the organic extract is removed. The residue is dissolved in THF:methanol 1:1 (5 mL) and is treated with Pd/C. The slurry is stirred at it for 16 h under 1.5 bar of H2. The mixture is filtered over celite and the filtrate is evaporated to give 3-[4-(2,3-dihydroxy-propyl)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (20 mg) as a colourless oil, LC-MS: tR=1.04 min, [M+1]+=423.28.
Reaction SMILES: CC(C)=O.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[N:28]O)[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.[OH-].[K+]>O>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[N:28][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=4)(=[O:38])=[O:37])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N=C2CCCc3nc(N4CCN(Cc5ccccc5)CC4)ncc32)cc1

Procedure:
Added to a mixture of 30 ml of acetone, 2 g (5.35 mmol, Referential Example 49) of 2-(4-benzylpiperazino)-5,6,7,8-tetrahydro-5-hydroxyiminoquinazoline, and 1.6 g (8.4 mmol) of p-toluenesulfonyl chloride was a solution of 0.7 g (11 mmol) of KOH in 10 ml of water. The resultant mixture was stirred at 20° C. for 4 hours.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][CH:40]=1>>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH:47][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:41][CH:40]=1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCCc1ccc(Cl)cc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(Cl)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-(4-chlorophenyl)-ethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 61% yield, m.p. 195-196° C. MS [(+)ESI, m/z]: 590.20 [M+H]+
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.C(Cl)(Cl)Cl>O>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:19])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Yield: 90 %

Procedure:
4-Hydroxymethylpyridine is hydrogenated in methanol at 140° C. under 200 atmospheres of hydrogen pressure in the presence of ruthenium oxide, producing 4-hydroxymethylpiperidine, b.p. 126°-130° C./14 mm Hg; m.p. 55°-56° C. Reaction with benzoyl chloride produces N-benzoyl-4-hydroxymethylpiperidine (m.p. 83°-85° C.). A mixture of 135.0 g of N-benzoyl-4-hydroxymethyl-piperidine, 90 ml of thionyl chloride and 900 ml of chloroform is heated under reflux for 4 hours. Thereafter, the reaction mixture is mixed with water, while cooling with ice, and the organic phase is washed neutral with an aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated. There are obtained 132.0 g (90% of theory) of N-benzoyl-4-chloromethylpiperidine; m.p. 68°-70° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 26.9 %

Procedure:
(±) cis-2-Ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (2.2 g, 10.8 mmol), 4-benzyloxyphenol (2.17 g, 10.8 mmol), p-toluenesulfonic acid (40 mg) were dissolved in toluene (50 ml) and heated at 60° C. for 5 h, then 2 h at reflux under nitrogen. On cooling, the reaction mixture was diluted with diethyl ether (150 ml) and washed sequentially with 10% aq. sodium hydroxide, water and brine. After drying over sodium sulfate, solvents were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (1.17 g) as a foam.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH:16](O)=[O:17].[CH2:19]([O:26][C:27](=[O:67])[N:28]([CH2:64][CH:65]=[CH2:66])[C:29]1[C:34](=[O:35])[N:33]2[C@H:36]([C:41](=[O:63])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:50]([NH:52][C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:54])=[NH:51])=[CH:46][CH:45]=3)[CH2:37][C@:38]([NH2:40])([CH3:39])[C:32]2=[N:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:67])[N:28]([CH2:64][CH:65]=[CH2:66])[C:29]1[C:34](=[O:35])[N:33]2[C@@H:36]([C:41](=[O:63])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:50]([NH:52][C:53]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)=[O:54])=[NH:51])=[CH:46][CH:45]=3)[CH2:37][C@@:38]([NH:40][CH:16]=[O:17])([CH3:39])[C:32]2=[N:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CO
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@]2(C)NC=O
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of DCC (18.6 mg, 0.090 mmol) and formic acid (8.28 mg, 0.180 mmol) in CH2Cl2 that had been stirred at 0° C. for 10 min, was added intermediate 26a (30 mg, 0.045) in a solution of pyridine. The reaction was stirred at 0° C. for 15m then at rt for 2 h. The reaction mixture was concentrated in vacuo, then taken up in brine and extracted with chloroform (6×), dried (Na2SO4) and concentrated. It was purified by SiO2 chromatography (gradient elution, 1–12% MeOH/CH2Cl2) to afford 23.3 mg (75%) of intermediate 42a. MS (ESI) 692.2 (M+H+).
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30](O)=[C:29]([Br:36])[CH:28]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:23][O:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:29]([Br:36])[CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)Cc1cc(Br)c(O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Trifluoromethanesulfonic acid t-butyldimethylsilyl ester (0.159 mL, 0.690 mmol) and triethylamine (0.120 mL, 0.863 mmol) were added to a solution of (3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic acid methyl ester (158 mg, 0.574 mmol) in dichloromethane (4 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (203 mg, 91%).
Reaction SMILES: C([N:3](CC)CC)C.ClC(OC)=O.[CH2:13]([N:20]1[C:28](=[O:29])[CH:27]2[CH:22]([C:23]3([C:31](O)=[O:32])[CH2:30][CH:26]2[CH:25]=[CH:24]3)[C:21]1=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N>[CH2:13]([N:20]1[C:28](=[O:29])[CH:27]2[CH:22]([C:23]3([C:31]([NH2:3])=[O:32])[CH2:30][CH:26]2[CH:25]=[CH:24]3)[C:21]1=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C2C3C=CC(C(=O)O)(C3)C2C(=O)N1Cc1ccccc1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: N
Product: NC(=O)C12C=CC(C1)C1C(=O)N(Cc3ccccc3)C(=O)C12
Temperature: 0 °C

Procedure:
1.1 g (11 mmol) of triethylamine and then 1.15 g (12 mmol) of methyl chloroformate are added dropwise to 3 g (10 mmol) of 4-benzyl-3,5-dioxo-4-azatricyclo[5.2.1.02,6 ]dec-8-ene-1-carboxylic acid in 20 ml of absolute tetrahydrofiran at 0° C. The mixture is stirred at 0° C. for a further hour and the solution is poured onto 20 ml of ammonia solution. The mixture is stirred at room temperature for 1 hour and extracted several times with chloroform, and the extracts are dried over MgSO4 and concentrated, whereupon the product crystallizes.
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([C:7]2=[N:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2].O.[H][H]>C(O)(=O)C>[CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([CH:7]2[NH:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2]
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Reactant: [H][H]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C1(C)C(=O)NC2c3ccccc3C(=O)N21

Procedure:
A solution of 1.2 g 3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H), 5-dione in 75 ml acetic acid and 10 ml water containing 100 mg 5% palladium on carbon is shaken in an atmosphere of hydrogen at a pressure of 10 psi and room temperature. One equivalent of hydrogen is absorbed in 75 minutes. The mixture is filtered, and the filtrate concentrated under reduced pressure. To the residue is added toluene which is then removed in vacuo. This is repeated. To the gummy residue is added a small volume of acetonitrile to give the desired 1,9b-dihydro-3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione as a crystalline solid identical to that prepared in Example 1.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Cc1ccnc(Br)c1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3cc(C)ccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 2-bromo-4-methylpyridine
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[S:23]1[C:27]([CH:28]=O)=[CH:26][N:25]=[CH:24]1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:28][C:27]1[S:23][CH:24]=[N:25][CH:26]=1)[CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: O=Cc1cncs1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2Cc1cncs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
To a solution of 1G (94 mg, 0.3 mmol) and thiazole-5-carbaldehyde (67.9 mg, 0.6 mmol) (prepared following the procedures described in Alessandro Dondoni, et al, Synthesis, 11, 998-1001, (1987)) in a mixed solvents of TFA (0.75 mL) and CH2Cl2 (0.75 mL) was added Et3SiH (0.096 mL, 0.6 mmol). The resulting mixture was stirred at RT under argon for 18 h, then concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3, then extracted with EtOAc (3×20 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (50-90%) in hexane to give the title compound as an off-white solid (70 mg, 57%). HPLC: 99% at 5.43 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4), Flow rate at 2.5 mL/min, UV detection at 220 nm). MS (ES): m/z 411 [M+H]+; Chiral HPLC 100% e.e.; retention time=32.9 min; Conditions: AD (4.6×250 mm); Eluted with 40% isopropanol in hexane for 50 min at 1 mL/min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCC(CO)C2)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CCN2CCC(COS(=O)(=O)c3ccc(C)cc3)C2)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.3 g (0.005 mol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-hydroxymethyl-pyrrolidine are dissolved in 10 ml of pyridine, 1.05 g (0 0055 mol) of p-toluenesulphonic acid chloride are added and the mixture is stirred for 6 hours at ambient temperature. The excess pyridine is then distilled off in vacuo, the residue obtained is dissolved in methylene chloride and the organic phase is extracted with ice water. After the organic phase has been dried over magnesium sulphate it is concentrated by evaporation in vacuo. Yield: 1.4 g (66.7% of theory), Rf value: 0.40 (aluminium oxide, neutral, eluant: 2% ethanol in methylene chloride).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:10]([SH:13])[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:21][CH2:22][CH2:23]Br.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:10]3[S:13][CH2:21][CH2:22][CH2:23][N:11]3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: Sc1[nH]nc(-c2cccc(Br)c2)c1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Yield: 50 %

Procedure:
5-(3-Bromo-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (60 mg, 0.22 mmol), 1,3-dibromopropane (22 ul, 0.22 mmol), K2CO3 (152 mg, 1.1 mmol) and dry DMF (5 ml) were reacted at room temperature for 16 hours. Water was added and the reaction extracted with ethyl acetate. The pooled organic extracts were washed with brine, dried over sodium sulphate and evaporated down. The crude material was purified by flash column chromatography eluting with ethyl acetate:hexane (1:1) to give a white solid (50% yield over two steps).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:31][N:32]1[C:38]2[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=2[CH:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:35]([NH2:50])[CH2:34][C:33]1=[O:51]>C(OCC)(=O)C>[CH3:31][N:32]1[C:38]2[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=2[CH:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:35]([NH:50][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:34][C:33]1=[O:51]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CN1C(=O)CN(N)C(c2ccccc2)c2cc(Cl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CN1C(=O)CN(NC(=O)CNC(=O)OCc2ccccc2)C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4.2 g. (0.02 moles) of benzyloxycarbonyl-glycine and 4.0 g. (0.02 moles) of dicyclohexyl carbodiimide are added to a solution of 6.0 g. (0.02 moles) of 1-methyl-4-amino-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 200 ml. of ethyl acetate. The reaction mixture is stirred at room temperature overnight, thereafter the separated dicyclohexyl urea is filtered off, and the filtrate is evaporated under reduced pressure. The residue is admixed with acetonitrile, the solution is boiled, the separated dicyclohexyl urea is filtered off from the hot solution, and the filtrate is allowed to cool. The separated crude product is filtered off, and crystallized from ethanol. 7.1 g. (72%) of 1-methyl-4-(N-benzyloxycarbonyl-glycylamino)-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 184°-190° C.; Rf(1) = 0.3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[OH:17])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:25][N:26]([CH3:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:25][N:26]([CH3:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:17][C:5]2[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[C:7]([NH:10][C:11](=[O:13])[CH3:12])[C:6]=2[N+:14]([O-:16])=[O:15])=[O:32])=[CH:29][CH:28]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(C)=O)c(OC(=O)c2ccc(N(C)C)cc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The imidazole flavonoid was prepared according to scheme 5. To a mixture of N-(4-acetyl-3-hydroxy-2-nitrophenyl)acetamide (1, 1 g, 4.1 mmol, 1.0 eq) and triethylamine (1.5 mL) was added 4-(dimethylamino)benzoyl chloride (2 hydrochloride, 6.3 mmol, 1.5 eq.) in 3 portions at 0° C. Then the mixture was stirred at rt for 3 h. Diluted with DCM (100 mL), washed with 1N HCl (100 mL) and water (50 mL). The organic phase was separated, dried with sodium sulfate, filtered and concentrated to afford gray solid, which was purified by SGC (PE/EA=1/1) to afford (3-acetamido-6-acetyl-2-nitrophenyl 4-(dimethylamino)benzoate (3), 1.2 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[O:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH:12]([NH:17]C(=O)OC)[CH2:11]1.[OH-].[K+]>CO.O>[NH2:17][CH:12]1[CH:13]([CH3:16])[CH2:14][CH2:15][N:10]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH:8]=[O:9])[CH2:11]1
Reactant: COC(=O)NC1CN(c2c(Cl)cccc2C=O)CCC1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CCN(c2c(Cl)cccc2C=O)CC1N
Temperature: 25 °C
Yield: 31.8 %

Procedure:
To a stirred solution of methyl 1-(2-chloro-6-formylphenyl)-4-methylpiperidin-3-ylcarbamate (220 mg, 0.71 mmol) (Method 119) in MeOH (3 ml) was added 40% aqueous solution of KOH (10 ml) drop wise, and the resulting mixture was heated at reflux for 16 h. The mixture was allowed to cool to rt, diluted with water, and extracted with DCM. The combined organic extract was dried over anhydrous Na2SO4, filtered, and conc. in vacuo. The resulting residue was purified via silica gel chromatography (100% ethyl acetate to 10% methanol in ethyl acetate) to yield the title compound as a light yellow gum (0.057 g, 31.9%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 (s, 1 H), 7.40 (t, 2 H), 7.07 (t, 1 H), 4.29 (d, 1 H), 3.58 (ddd, 1 H), 3.38 (dd, 1 H), 3.11 (td, 1 H), 2.81 (d, 1 H), 2.20-1.91 (m, 1 H), 1.31-1.14 (m, 1 H), 1.08 (d, 3 H), 0.63-0.37 (m, 1 H).