Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1.[CH3:19][C:20]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.I[C:61]1[NH:65][C:64]([C:66]2([CH3:70])[CH2:69][O:68][CH2:67]2)=[N:63][C:62]=1[C:71]#[N:72].IC1NC(C)=NC=1C>>[C:71]([C:62]1[N:63]=[C:64]([C:66]2([CH3:70])[CH2:67][O:68][CH2:69]2)[NH:65][C:61]=1[C:27]1[C:28]([CH3:30])=[CH:29][C:20]([CH3:19])=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])#[N:72]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: CC1(c2nc(C#N)c(I)[nH]2)COC1
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1cc(-c2[nH]c(C3(C)COC3)nc2C#N)c(C)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) and 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound 202.3) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 326 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([O:23][C:24]([F:27])([F:26])[F:25])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:19])([F:18])[F:17])[C:12]([C:20]([OH:22])=[O:21])=[CH:11]2)[CH3:2].[OH:28]S(O)(=O)=O>CC(C)=O.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([O:23][C:24]([F:25])([F:27])[F:26])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:17])([F:18])[F:19])[C:12]([C:20]([OH:22])=[O:21])=[CH:11]2)[CH3:2]
Reactant: CCOC#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 198.8 %

Procedure:
To a solution of the crude product from Step 1 (2.13 g) in a mixture of acetone (80 mL) and H2O (10 mL) was added H2SO4 (0.250 g, 2.55 mmole) and the resulting mixture was stirred at room temperature for 2.5 hrs. Brine (200 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2.10 g of the crude product as a yellow oil: ESLRMS m/z 414.0 (M+H, C16H12F6O6, Calc'd 415.0).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][C:9](O)=O.O.N>S(=O)(=O)(O)O>[Cl:6][CH2:7][CH2:8][C:9]1[S:4][C:3]([NH2:5])=[N:2][N:1]=1
Reactant: NNC(N)=S
Reactant: O=C(O)CCCl
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nnc(CCCl)s1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Thiosemicarbazide (10 g, 111 mmol) is added in portions to a solution of 3-chloropropionic acid (10 g, 92 mmol) in concentrated sulfuric acid. The mixture is heated with stirring at 75° C. for 1 hour. After cooling to room temperature the reaction mixture id added slowly to water and the resulting solution is brought to pH 7 by addition of aqueous ammonia solution. The titled product precipitates as a yellow solid which is removed by filtration and dried.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:7]=[CH:6]1)([CH3:4])[CH3:3].C(OC(=O)C)(=[O:21])C>>[CH3:1][C:2]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([OH:21])[C:8]=2[N:7]=[CH:6]1)([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)n1cnc2c[n+]([O-])c3ccccc3c21
Product: CC(C)(C)n1cnc2c(O)nc3ccccc3c21
Temperature: 20 °C

Procedure:
To 50 mL of acetic anhydride was added 11.5 g (0.0477 mole) of 1-(1,1-dimethylethyl)-1H-imidazo-[4,5-c]quinoline-5oxide (produce of Example 25) and the slurry was heated on a steam bath for a few minutes, then allowed to cool to about 20° C. The solid was separated by filtration and washed with an ethanol-hexane mixture. Slurrying with dilute ammonium hydroxide, filtration and washing with water provided solid which has recrystallized from an ethanol-dichloromethane mixture to provide colorless (white) crystals of 1-(1,1-dimethylethyl)-1H-imidazo[4,5-c]quinolin-4-ol, m.p. greater than 300° C. Analysis: Calculated for C14H15N3O: %C, 69.7; %H, 6.3; %N, 17.4; Found: %C, 69.5; %H, 6.3; %N, 17.3.
Reaction SMILES: [CH2:1]([N:4]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:7]([F:18])[CH:6]=1)[CH:2]=[CH2:3].[I-:29].O1CCNC1=O>>[I:29][CH2:3][CH:2]1[O:20][C:19](=[O:21])[N:4]([C:5]2[CH:6]=[C:7]([F:18])[C:8]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[C:9]([F:11])[CH:10]=2)[CH2:1]1
Reactant: [I-]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(F)c(-c2ccncc2)c(F)c1
Agent: O=C1NCCO1
Product: O=C1OC(CI)CN1c1cc(F)c(-c2ccncc2)c(F)c1

Procedure:
Following the general procedure of PREPARATION 5 and making non-critical variations but starting with N-allyl-N-carbobenzyloxy-4-(4-pyridyl)-3,5-difluoroaniline (PREPARATION 10, 241 mg, 0.634 mmol) is converted to the oxazolidinone iodide. The crude product is not purified further, NMR (CDCl3) δ 8.70, 7.44, 7.32, 4.85-4.73, 4.19, 3.80, 3.50, 3.40.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:16][CH2:17][CH2:18][Cl:19])[C:6]([O:8]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH:5]([CH2:16][CH2:17][CH2:18][Cl:19])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CCCCl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC(CCCCl)C(=O)O
Yield: 94.7 %

Procedure:
Benzyl 2-acetoxy-5-chloropentanoate (52.6 g, 0.19 mol) was dissolved in ethyl acetate (350 ml) and acetic acid (25 ml) and hydrogenated at 10 psi in a Parr apparatus in the presence of a Pd/C catalyst (5%, 2.5 g). After completion, the catalyst was filtered off and the volatiles were evaporated. The residue was dried in vacuo (1 mm Hg, 100° C.), and 35 g (98%) of the crude product was isolated and used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 128 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-bromodecane and conditions outlined in procedure V. M.p.=110-111° C.; 400 MHz 1H NMR (CDCl3) δ 8.06 (d, J=1.2 Hz, 1H), 7.8-7.75 (m, 1H), 7.75-7.6 (m, 1H), 7.53-7.43 (m, 1H), 2.93 (s, 2H) 2.85-2.75 (m, 2H), 2.5-2.35 (m, 4H), 2.2-2.05 (m, 2H), 1.95-1.8 (m, 2H), 1.6-1.43 (m, 2H), 1.4-1.18 (m, 14H), 0.9-0.8 (m, 3H); LCMS: 442 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:15]=2[N:16]=1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([N:8]([C:13]12[CH2:22][C:17]3([CH3:23])[CH2:18][CH:19]([CH2:21][C:15]([CH3:24])([CH2:16]3)[CH2:14]1)[CH2:20]2)[CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-:25][Mn](=O)(=O)=O.[K+].Cl>[OH-].[K+].O.CCOC(C)=O>[C:1]([N:8]([C:13]12[CH2:14][C:15]3([CH3:24])[CH2:16][C:17]([CH3:23])([CH2:18][C:19]([OH:25])([CH2:21]3)[CH2:20]1)[CH2:22]2)[CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC12CC3CC(C)(C1)CC(N(CC(=O)O)C(=O)OC(C)(C)C)(C3)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC12CC3(C)CC(O)(C1)CC(N(CC(=O)O)C(=O)OC(C)(C)C)(C2)C3
Temperature: 90 °C
Yield: 102 %

Procedure:
To a solution of N-BOC-(3,5-dimethyladamantan-1-yl)-glycine (1.79 g, 5.3 mmol) in 2% KOH/water (75 mL) at rt was added KMnO4 (1.0 g, 6.3 mmol). The reaction was heated to 90° C. for 2 h. An additional portion of KMnO4 (0.3 g, 1.9 mmol) was added and the reaction was heated at 90° C. for an additional 1.5 h. The reaction was then diluted with EtOAc (150 mL) and with vigorous mixing the pH was addjusted to ˜3 with 1N HCl. The EtOAc layer was separated and set aside. The aqueous layer was then extracted once more with EtOAc and twice with dichloromethane. The combined organics were dried over MgSO4, filtered and concentrated to give N-BOC-(3-hydroxy-5,7-dimethyladamant-1-yl)-glycine (1.91 g). MS m/e (M+H)+=354.2
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](O)[CH2:8][CH2:9]C.BrCCCCl.[CH:17]([NH2:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C1(C)C=CC=CC=1>[CH:17]([N:30]1[CH2:9][CH2:8][CH2:7]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCO
Reactant: NC(c1ccccc1)c1ccccc1
Agent: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(C(c2ccccc2)N2CCC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To A solution of 6.9 kg (50 moles) of potassium carbonate in 7.5 liters of water was added 18.5 liters of 1-butanol, 7.85 kg (50 moles) of 1-bromo-3-chloropropane and 5.18 kg (25 moles) of benzhydrylamine (97% purity with 10% toluene as a residual solvent). The reaction mixture was heated to 100° C. externally with steam and stirred slowly under a nitrogen gas atmosphere overnight. About 12 liters of water was added to the mixture to dissolve some inorganic salt precipitate. The layers were separated and organic layer was distilled under reduced pressure to remove about 18 liters of butanol and water. To the residue was added 1.5 liters of methanol and the resulting mixture was stirred slowly while cooling down to room temperature. The white solid was collected by filtration, rinsed twice with 700 ml portions of methanol and dried in a vacuum oven to give 4.2 kg (75%) of product, m.p. 107°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4OC)CC3)nc2c1
Yield: 84 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): δ 3.15 (s, 4H), 3.83-3.89 (m, 9H), 4.12-4.17 (m, 4H), 6.88-6.95 (m, 3H), 7.02-7.05 (m, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.31 (s, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[C:24](Cl)=[N:25][CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)C(C)C)C.C(N(CCC)CCC)C>C(O)CCC>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([N:25]4[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH2:24]4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: Fc1cccnc1Cl
Agent: CCCN(CC)CCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: FC1=CC=CN(N2CCC(C3c4ccccc4C=Cc4ccccc43)CC2)C1
Reaction time: 24 h

Procedure:
0.50 gram (1.82 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 0.24 gram (1.82 millimoles) of 3-fluoro-2-chloropyridine, 0.47 gram (3.64 mole) of ethyl diisopropylamine and 10 milliliters of n-butanol were heated at reflux temperature protected from atmospheric moisture with a drying tube. After 19.25 hours heating, an additional 240 milligrams of the 3-fluoro-2-chloropyridine was added. After another 24 hours, 300 milligrams of ethyl dipropylamine was added and heating continued. After about 140 hours of refluxing, the mixture was concentrated, diluted with ether, washed successively with 10 percent aqueous sodium hydroxide and brine, dried, and the solvent vaporized to obtain a brown semi-solid residue. The residue was purified by chromatographing on silica gel with 7 percent ether in hexanes to obtain the 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(3-fluoro-1-pyridyl)piperidine product as a crystalline white solid, which after drying overnight in vacuo and 4 hours at 100° C. at 1 millimeter of mercury pressure had a melting point of 208°-210° C. Elemental analyses were as follows:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][C:16]([CH3:18])=O.N1CCCC1>CO>[CH3:15][C:16]1([CH3:18])[CH2:13][C:12](=[O:14])[C:3]2[C:2](=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1O
Reactant: CC(C)=O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccc(C(F)(F)F)cc2O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75.5 %

Procedure:
The crude 1-[2-hydroxy-4-(trifluoromethyl)phenyl]ethanone (9.90 g, 48.5 mmol) from above was dissolved in methanol (100 mL) and acetone (3.56 mL, 48.5 mmol), and pyrrolidine (8.02 mL, 97.0 mmol) were added. The reaction was stirred at ambient temperature for 14 h; LCMS showed reaction completion. The reaction mixture was concentrated and diluted with EtOAc (300 mL), then washed with water (100 mL), 2N HCl (2×100 mL), water (50 mL), 2N NaOH (2×100 mL), water (50 mL), and brine (20 mL). The organic portion was dried (Na2SO4), filtered, concentrated, and the residue purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to give the title compound (8.93 g, 36.6 mmol, 75%) as a white solid. MS (ESI) m/z 245 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[C:12](Br)[CH:13]=4)[C:4]=2[CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:15]1([CH3:22])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:7]=[CH:6][C:5]=4[N:8]3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=3)[CH:11]=[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:13]=2
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cc(Br)cc1c32
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)c2ccccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32

Procedure:
19.8 g (45 mmol) of 3,6-dibromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine, 11.4 g (94 mmol) of phenylboronic acid and 164 ml of saturated NaHCO3 solution are suspended in 1500 ml of toluene and 150 ml of ethanol. 1.9 g (1.6 mmol) of Pd(PPh3)4 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness.
Reaction SMILES: C(OC(=O)[C@H](CO)N[C:9](=[O:29])[CH2:10][N:11]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]1[C@@H:27]2[C@@H:22]([NH:23][C:24]([NH:26]2)=[O:25])[CH2:21][S:20]1)[CH3:12])(C)(C)C.C(N(CC)CC)C.C1(=O)O[C:43](=[O:44])CC1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:43][O:44][C:9](=[O:29])[CH2:10][N:11]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]1[C@@H:27]2[C@@H:22]([NH:23][C:24]([NH:26]2)=[O:25])[CH2:21][S:20]1)[CH3:12]
Reactant: O=C1CCC(=O)O1
Reactant: CN(CC(=O)N[C@@H](CO)C(=O)OC(C)(C)C)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 12.5 °C
Reaction time: 22 h

Procedure:
To a solution of biotinamido-N-methylglycyl-serine t-butyl ester (6) in anhydrous dimethylformamide is added 3 equivalents of triethylamine, 0.01-0.1 equivalents of 4-dimethylaminopyridine and 1.1 equivalents of succinic anhydride. The mixture is stirred at 0-25° C. for 20-24 h and then concentrated via reduced pressure rotary evaporation. The residue is diluted with ethyl acetate and 1 N aqueous hydrochloric acid. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed on reverse phase C-18 silica gel, eluting with methanol/water. The fractions containing the product are combined and concentrated to give the final product (4).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:11]>C(Cl)Cl>[NH:4]1[C@H:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]2[NH:11][C:1]1=[S:3]
Reactant: S=C=S
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Product: S=C1N[C@H]2CCCC[C@H]2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of carbon disulfide (1.1 mL, 17.9 mmol) and CH2Cl2 (10 mL) was treated dropwise with cis-1,2-diaminocyclohexane 20-1 (Aldrich) (2.0 g, 17.5 mmol) while maintaining the reaction mixture temperature below 20° C. with an ice bath. The reaction mixture was stirred at ambient temperature for 2.0 h after the addition was complete. Concentration followed by refluxing the resulting solid in H2O (20 mL) for 20 h gave a yellow solution. The cooled solution was extracted with CH2Cl2 and the CH2Cl2 portion was dried (MgSO4) and concentrated. The pale yellow solid was recrystallized from CH2Cl2 /ether to give 20-2 as a pale yellow solid. mp=164°-166° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[SH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([S:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:3][C:4]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][CH:11]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
A 25 mL round-bottomed flask was charged with 5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (350 mg, 0.966 mmol), Pd2dba3 (22.1 mg, 0.024 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9 mg, 0.048 mmol), N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.9 mmol), methyl 3-mercaptopropanoate (0.12 mL, 1.1 mmol), and dioxane (10 mL). The reaction mixture was heated to 100° C. under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to afford the title compound (328 mg, 84.5% yield) as a pale yellow solid. HCl salt made for characterization. 1H NMR (d6-DMSO) δ 8.18 (d, 1H), 7.45 (m, 2H), 7.36 (d, 1H), 7.22 (t, 1H), 7.13 (d, 2H), 6.79 (s, 1H), 3.55 (s, 3H), 3.07 (t, 2H), 2.57 (t, 2H), 2.29 (s, 3H); Mass spectrum (esi) m/z=402.2 (100)(M+H—HCl).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1F

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3,4 difluorobenzaldehyde. MS (ESI) m/z 505.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[O:5][C:6]=1[CH2:7][CH2:8][OH:9].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.N1C=CC=CC=1>O>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:9][CH2:8][CH2:7][C:6]2[O:5][C:4]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3)=[N:3][C:2]=2[CH3:1])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1cc(-c2nc(C)c(CCO)o2)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(-c2nc(C)c(CCOS(=O)(=O)c3ccc(C)cc3)o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the solution of 2-[4-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-5-yl]ethanol (2.93 g, 10 mmol) in 30 ml of pyridine 4-toluenesulfonyl chloride (1.9 g, 10 mmol) was added portionwise at room temperature. Subsequently, the reaction mixture was stirred for 5 h at room temperature, and then poured into 200 ml of water and extracted (3×) with 50 ml of dichloromethane. The combined extracts were washed with 1M HCl, an aqueous solution of sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated, to obtain a product, 2-[4-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-5-yl]ethyl 4-toluenesulfonate having the purity of ca. 95%.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([OH:15])=[O:14])[NH:8]2.Cl.N.[CH3:18]O>>[CH3:18][O:14][C:13]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH3:2])[NH:8]1)=[O:15]
Reactant: CO
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Agent: Cl
Agent: N
Agent: [Mg]
Product: COC(=O)C1Cc2c(cccc2OC)N1
Temperature: 110 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
119 mg (4.90 mmol) of magnesium turnings are added to a solution of 500 mg (2.44 mmol) of 4-methoxy-1H-indole-2-carboxylic acid in 10 ml of methanol. The mixture is stirred for 3 hours in a bath at 110° C. and then for 1 hour at room temperature. 20 ml of hydrochloric acid are added at 0° C. and the mixture is stirred for one hour. 3 N ammonia solution is then added to pH 10 and the mixture is extracted with 3 times 50 ml of ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column using a dichloromethane/ethyl acetate mixture (98/5, then 95/5; v/v) as the eluent to give the expected product in the form of a brown oil with a yield of 64%.