Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Li+].C1COCC1.Cl>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (0.706 g, 1.518 mmol), lithium hydroxide (0.0545 g, 2.28 mmol), THF (60 mL), and water (20 mL) were combined and stirred under argon at room temperature overnight. Solvents were pumped off, and the residue taken up in water (20 mL). The mixture was acidified with HCl until it appeared that no more precipitate was forming. The pH at this time was about 6. The solid was filtered off and washed 2× with a small volume of water. The material was dried under vacuum for two days until weight loss was minimal to give the title compound as a white solid. LC-MS m/z 451.8 (M+H)+, 1.48 min (ret time); mp 207-209° C.; analytical HPLC shows 100% purity, (ret time 10.177 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C1(C)C=CC=CC=1.CC(O)C>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reaction time: 12.5 h
Yield: 99.8 %

Procedure:
A mixture of tert-butyl 4-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}butylcarbamate (30.0 g, 64.3 mmol) and 5% platinum on carbon (3.0 g) in toluene (675 mL) and 2-propanol (100 mL) was hydrogenated on a Parr apparatus for 12.5 hours at 24 psi (1.7×105 Pa). The mixture was filtered through CELITE filter agent, which was rinsed afterwards with 1:1 toluene/2-propanol and 2-propanol. The combined filtrates were concentrated under reduced pressure to afford 28 g of tert-butyl 4-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}butylcarbamate as a viscous black oil that was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][NH2:12]>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(Br)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(Br)n1
Reaction time: 0.25 h

Procedure:
A solution of 6-bromopicolinoyl chloride (Example 69A, 350 mg, 1.6 mmol) in tetrahydrofuran (4 mL) was added in portions via a pipette over 2 minutes to a solution of methylamine (40 wt. % in water, 4 mL, 46.2 mmol) in tetrahydrofuran (6 mL). The mixture was stirred for 15 minutes and partitioned between water (5 mL) and CH2Cl2 (25 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered and concentrated to provide the desired product, 6-bromo-N-methylpicolinamide. 1H NMR (300 MHz, CDCl3) δ ppm 3.03 and 3.04 (s and s, 3H), 7.45 and 7.60 (dd and dd, J=8.1, 1.0 Hz, 1H), 7.71 and 7.82 (t, J=7.8 Hz, 1H), 7.75-7.88 (bs, 1H), 8.11-8.18 (m, 1H); MS (DCI/NH3) m/z 215 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][N:3]2[C:4]3=[N:9][C:8]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[CH:7][C:6](=[O:16])[N:5]3[CH2:17][C@@:2]2([CH3:1])[C:18]([F:21])([F:19])[F:20])[CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: Clc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCc1cccc(Cl)c1

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 87 mg of 1-(2-bromoethyl)-3-chlorobenzene, replacing the sodium hydride with 214 mg of caesium carbonate. After purification by preparative HPLC/MS (method C), 38 mg of (2S)-1-[2-(3-chlorophenyl)ethyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[C:9]1(/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH2:23].CC(C)=O.C(#N)C>O=[Os](=O)(=O)=O>[C:9]1([CH:15]([OH:5])[CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[OH:23])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: CC#N
Product: OC(c1ccccc1)C(O)c1ccccc1
Yield: 93 %

Procedure:
Resin-OsO4 (0.01 Eq. Wt.), N-methylmorpholine-N-oxide (1.5 Eq. Wt.) and trans-stilbene (1.0 Eq. Wt) in the mixed solvent of water/acetone/acetonitrile (in the volume ratio of 1:1:1) were stirred at room temperature for 6 hours. After completion of the reaction, the catalyst was filtered off and washed with ethyl acetate. Combined filtrates were concentrated under reduced pressure. The pure product, 1,2-diphenyl-1,2-ethandiol was obtained by removing the solvent at reduced pressure followed by column chromatography. (yield 93%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6](S(C)(=O)=O)[N:5]=1)([CH3:3])[CH3:2].Cl.[C@@H:20]12[CH2:26][C@@H:23]([CH2:24][CH2:25]1)[CH2:22][C@@H:21]2[NH2:27].O1CCOCC1.C(N(CC)C(C)C)(C)C>O>[C@@H:20]12[CH2:26][C@@H:23]([CH2:24][CH2:25]1)[CH2:22][C@@H:21]2[NH:27][C:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1C(C)C
Reactant: N[C@H]1C[C@@H]2CC[C@H]1C2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N[C@H]2C[C@@H]3CC[C@H]2C3)nc1C(C)C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a mixture of ethyl 4-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (400 mg), (1S,2S,4R)-bicyclo[2.2.1]heptan-2-aminehydrochloride (347 mg), and 1,4-dioxane (8 mL) was added N,N-diisopropyl ethylamine (1 mL) at room temperature, followed by stirring at the same temperature for 16 hours. To the reaction mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain ethyl 2-[(1S,2S,4R)-bicyclo[2.2.1]hept-2-ylamino]-4-isopropylpyrimidine-5-carboxylate (417 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=1)([CH3:7])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>CO.O1CCCC1.O>[CH3:7][C:2]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)Oc1cc(C(F)(F)F)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(Oc1cc(C(F)(F)F)ccn1)C(=O)O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 2-methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionate (Step B, 7.5 g, 29 mol) in 50 mL of methanol, 50 mL of tetrahydrofuran and 50 mL of water was added sodium hydroxide (2.3 g, 57 mmol). After stirring at 50° C. for 5 h, the reaction mixture was partially concentrated, and was added 2 M hydrochloric acid to pH >2. The resulting mixture was extracted with ethyl acetate (2×200 mL), and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.28 (d, 1H), 7.17 (d, 1H), 7.05 (s, 1H), 1.70 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][S:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[S:34]1[C:30]2[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:39][CH:38]=3)=[O:24])[C:31]=2[CH:32]=[CH:33]1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3sccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3sccc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 4,10-dihydro-4-(4-aminobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e]-[1,4]diazepine. The mixture is stirred for 5 hours. The reaction mixture is washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. 162°-188° C. (amorphous)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[ClH:11].CCOCC.Cl.[Cl:18]N1C(=O)CCC1=O>CCOCC.Cl.C(O)(=O)C>[ClH:18].[Cl:11][CH2:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1cnccc1C
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccncc1C(=O)CCl
Yield: 83.2 %

Procedure:
In a 500 mL round bottom flask was placed 1-(4-methyl-3-pyridinyl)ethanone (10.0 g, 74.1 mmol) in 90 mL of Et2O. To this solution was added 88.9 mL of 1M HCl/Et2O (1.2 eq, 88.9 mmol) with stirring and the solution allowed to stir for 1 h at room temperature, at which point, the precipitate was filtered and washed with Et2O. The solid was then dried in vacuo at about 60° C. This HCl salt (12. g, 70.0 mmol) was then dissolved in 70.0 mL of 1M HCl/acetic acid where 9.34 g (1 eq. 70.0 mmol) of N-chlorosuccinimide (NCS) was added and the reaction allowed to stir under Argon at room temperature overnight. At this point, 300 mL of Et2O was added resulting in an off-white precipitate. This was allowed to stir for 1 h at which point the solid was filtered and rinsed with Et2O to provide 12.0 g (83%) of the desired 2-chloro-1-(4-methyl-3-pyridinyl)ethanone hydrochloride. GC/MS RT=6.60 min; 1H-NMR (DMSO-d6) δ 2.51 (s, 3H), 5.15 (s, 2H), 7.68 (d, 1H), 8.68 (d, 1H), 9.06 (s, 1H); [M]+169 (95%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4].C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:25])[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Temperature: 60 °C
Yield: 74.6 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid methyl ester (0.43 g, 1.6 mmol) (as prepared in the previous step) in CCl4 (10 mL) was added NBS (0.30 g, 1.7 mmol) and AIBN (cat) and the mixture heated at 60° C. for 4 h. The reaction was diluted with EtOAc (30 ml) and washed with satd NaHCO3 (2×30 mL) and brine (30 mL) and the organic layer concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 50% EtOAc/hexane to give 0.40 g (71%) of a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C11H19BrN2O3Si, 335.0/337.0 (M+H), found 335.0/337.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][N:38]([CH3:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][N:38]([CH3:46])[CH3:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)CCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCCCCN(C)C)cc3C)c2cc1OC
Yield: 62.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 6-(dimethylamino)-1-hexanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 56%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][CH:9]=O)[CH:2]=1.[NH2:11][C:12]1[S:13][C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20]=2[N:21]=1.C([BH3-])#N.[Na+]>>[NH2:11][C:12]1[S:13][C:14]2[CH2:15][CH2:16][N:17]([CH2:9][CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:18][CH2:19][C:20]=2[N:21]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: O=CC=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: Nc1nc2c(s1)CCN(CC=Cc1cccnc1)CC2
Yield: 40 %

Procedure:
Prepared from 3-(3-pyridyl)acrolein and 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine by reductive amination with sodium cyanoborohydride. Yield: 40% of theory, Melting point: 162°-165° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1)[CH2:9][NH:10][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(CN)Cc1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)Cc1ccc(O)c(C(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
To a solution of 1.53 g (4.75 mmol) of [2-amino-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]carbamic acid tert-butyl ester in methylene chloride (20 ml), 0.725 ml (5.23 mmol) of triethylamine and 0.746 ml (5.23 mmol) of benzyl chloroformate were added and the resulting mixture was stirred for 15 minutes. Under cooling with ice, saturated aqueous NaHCO3 was added and the mixture was extracted with methylene chloride and washed with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=1:1) to give [2-(benzoxycarbonylamino)-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]carbamic acid tert-butyl ester in the amount of 1.78 g (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([NH2:12])[C:10]#[CH:11].C(NC(C)C)(C)C>C(Cl)Cl.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][NH2:12])=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: Clc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: NCC#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro iodobenzene (25 g) in 400 mL CH2Cl2 at room temperature was added propargyl amine (13.5 mL), diisopropyl amine (37 mL), CuI (4 g) and Pd(PPh3)2Cl2 (3.7 g). The mixture was stirred overnight at room temperature, diluted with 600 mL EtOAc and filtered through a CELITE pad to remove insoluble materials. The solution washed with water, brine, dried over MgSO4, concentrated and purified by chromatography to provide 14.1 g of 3-(4-chloro-phenyl)-prop-2-ynylamine. MS: m/e 166.1 (MH+)
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 61.3 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.13 g of sodium ethoxide was added thereto. A solution of 4.7 g of tetradecyl bromide in 20 ml of ethanol was added to the mixed solution while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. Then, the mixture was neutralized with a 1 N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 3.5 g of diethyl 2-acetamido-2-tetradecylmalonate.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([CH3:22])[C:12]=2Cl)[CH2:5][CH2:4]1.[CH:27]12[CH2:32][CH:31]1[CH2:30][NH:29][CH2:28]2.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([CH3:22])[C:12]=2[N:29]2[CH2:30][CH:31]3[CH:27]([CH2:32]3)[CH2:28]2)[CH2:5][CH2:4]1
Reactant: C1NCC2CC12
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC3CC3C2)c1C

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-3-methyl-4-methylamino-5-nitro-benzoic acid amide (250 mg, 0.64 mmol), 3-aza-bicyclo[3.1.0]hexane (151 mg, 1.27 mmol), DIPEA (0.44 mL, 2.5 mmol) and dioxane (8 mL). Yield: 130 mg. HPLC Rt=1.62 min (method H). MS m/z: 441 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[Br:1][C:2]1[C:3]([O:13][CH:15]([CH3:17])[CH3:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2ccc(O)c(Br)c2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc2ccc(OC(C)C)c(Br)c2n1
Temperature: 70 °C

Procedure:
A mixture of 8-bromo-2-methylquinolin-7-ol (0.093 g, 0.39 mmol), 2-iodopropane (0.078 mL, 0.78 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in acetone (1.6 mL, 0.39 mmol) was heated at 70° C. for 12 hours. After cooling, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by normal phase chromatography on silica (10% ethyl acetate/hexanes) provided the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:16]=[O:17].O>CO.C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:16][OH:17])[C:11](=[O:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(-n2oc(=O)[nH]c2=O)c1
Reactant: C=O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CSc1cccc(-n2oc(=O)n(CO)c2=O)c1
Reaction time: 2 h

Procedure:
2-(3-methylthiophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3-methylthiophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1C=CC=CC=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].ON1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:55][C:56]1[S:60][C:59](=[S:61])[NH:58][N:57]=1>>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1]([NH:18][C@H:19]([C:27]([NH:55][C:56]3[S:60][C:59](=[S:61])[NH:58][N:57]=3)=[O:28])[CH2:20][CH2:21][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:2])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: On1nnc2ccccc21
Reactant: Nc1n[nH]c(=S)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(N[C@@H](CCc1ccccc1)C(=O)Nc1n[nH]c(=S)s1)OCC1c2ccccc2-c2ccccc21

Procedure:
Fmoc-phenylalanine (0.8 grams), 1-hydroxybenzotriazole (0.38 grams), dicyclohexylcarbodiimide (0.4 grams) and 5-amino-1,3,4-thiadiazole-2-thione (0.4 grams) were reacted according to the procedure described in Example 1. The resulting product was recrystallized from ethanol/pentane to give a white powder. M.P. 186°-187° C. NMR spectrum (d6 -DMSO) 14.08 (s, 1H), 12.6 (s, 1H), 8.00-7.1 (m, 14 H, NH+aromatics), 4.4-4.1 (m, 4H), 2.8-2.3 (m, 2H), 2.1-1.8 (m, 2H).