Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1>[Pt].OC1C=C(C=C(O)C=1)C(O)=O.C(C(CC)=O)C>[CH3:4][CH2:3][CH:2]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1)[CH2:7][CH3:6]
Reactant: Cc1ccc(N)cc1C
Agent: [Pt]
Agent: O=C(O)c1cc(O)cc(O)c1
Solvent: CCC(=O)CC
Product: CCC(CC)Nc1ccc(C)c(C)c1
Temperature: 70 °C
Yield: 150.2 %

Procedure:
A Parr hydrogenation apparatus was charged with 1.2 grams 5% platinum on carbon, 0.62 g 3,5-dihydroxybenzoic acid (pKa=1.92), 24.2 grams 3,4-xylidine and 28.0 grams diethyl ketone. The mixture heated to 70° C. and hydrogenated at 35-60 psig. The mixture was cooled, filtered, the filter cake washed with methanol, and the organic phase (87.7 g) analyzed by gas-liquid chromatography. Thus, 28.7 g of N-3-pentyl-3,4-xylidine was obtained, corresponding to a yield of 75.1%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[N:16][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]2)[CH:15]=[N:16][CH:17]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
1-(4-Hydroxy-piperidin-1-yl)-ethanone (200 mg, 1.4 mmol) and 5-bromo-pyridin-3-ol (248 mg, 1.4 mmol) are added to a solution of PPh3 (606 mg, 2.3 mmol) in THF (30 mL). Then diisopropyl azodicarboxylate (462 mg, 2.3 mmol) is added and the mixture is stirred at room temperature for 16 hrs. The mixture is then diluted with DCM, washed with water, dried over Na2SO4, filtered and concentrated. The residue is purified by flash column chromatography to give 250 mg of 1-[4-(5-bromo-pyridin-3-yloxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[OH-].[NH4+:14].C(O)C>C(OCC)(=O)C>[NH2:14][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc([N+](=O)[O-])cnc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Into a 250 mL sealed tube were combined 2-chloro-3-methoxy-5-nitropyridine (0.50 g, 0.00265 mol), concentrated ammonium hydroxide (5 mL, 0.1 mol) and ethanol (20 mL). The mixture was heated to 80° C. and stirred overnight. After allowing to cool to room temperature, the mixture was reduced in vacuo and the residue was taken up in ethyl acetate (50 mL), then washed with equal amounts of brine and water (1×50 mL each). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum to leave a solid (0.312 g, 69%) which was used directly in the next step without further purification. LC-MS 1.94 min. M/Z=171.0 (M+1).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:13]([OH:30])[C@@H:14]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([NH:7][CH:8]([CH3:12])[CH2:9][CH2:10][CH3:11])=[O:6])=[N+]=[N-]>CO>[NH2:1][C@@H:4]([C@@H:13]([OH:30])[C@@H:14]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([NH:7][CH:8]([CH3:12])[CH2:9][CH2:10][CH3:11])=[O:6]
Reactant: CCCC(C)NC(=O)[C@@H](N=[N+]=[N-])[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Product: CCCC(C)NC(=O)[C@@H](N)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of (2S,3S,4S)-2-azido-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-N-(1-methylbutyl)-5-phenylpentanamide (55 mg, 0.131 mmol) in MeOH (4 mL) which had been degassed and purged with nitrogen was added a small amount of 10% Pd on carbon. The mixture was flushed again with nitrogen and stirred overnight under a balloon atmosphere of hydrogen. The reaction was filtered and the resulting filtrate concentrated in vacuo to afford the product as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.25-7.23 (m, 4H), 7.17-7.15 (m, 1H), 3.91-3.86 (m, 2H), 3.66-3.59 (m, 1H), 3.32-3.30 (m, 1H), 3.21-3.17 (m, 1H), 2.59-2.52 (m, 1H), 1.52-1.33 (m, 4H), 1.29 (s, 9H), 1.26-1.12 (m, 3H), 0.95-0.91 (m, 3H); ES MS (M+1)=394.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].Cl.[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)#[CH:33]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:33]=[C:32]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1ccncc1
Agent: Cl
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccncc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 17 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 4-ethynyl pyridine hydrochloride (Aldrich) in the same manner as Example 15. ESI MS m/z 535 [C27H30N6O4S+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C)C=O.CCCCCC>[Si:14]([O:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C1CC[C@H](CO)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1
Reaction time: 5 h
Yield: 107.5 %

Procedure:
Under atmosphere of argon, a solution of (5R)-5-hydroxymethylpyrollidin-2-one (10 g) and imidazole (8.8 g) in dry dimethylformamide (50 mL) was added by a solution of t-butyldimethylsilyl chloride (15.6 g) in dry dimethylformamide (50 mL) at room temperature, and the mixture was stirred for 5 hours. To the mixture, a mixed solvent of ethyl acetate and hexane was added. The diluted solution was washed with water and brine successively, dried over an anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound (21.41 g) having the following physical data.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:8][C:7]=1[N+:17]([O-])=O>C(O)C.[C].[Pd]>[NH2:17][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:6]=1[NH:5][CH2:4][CH2:3][N:2]([CH3:20])[CH3:1])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11]
Reactant: CN(C)CCNc1ccc(C(=O)N(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCNc1ccc(C(=O)N(C)C)cc1N
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 103.3 %

Procedure:
10% of palladium-carbon (0.535 g) was added to a solution containing 4-{[2-(dimethylamino)ethyl]amino}-N,N-dimethyl-3-nitrobenzamide (2.672 g) in ethanol (27 ml) and the mixture was stirred for 5.5 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated, thereby yielding the entitled compound (2.464 g) as blackish brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][CH2:27][CH3:28])=[N:8][N:9]([C:12]2[CH:17]=[C:16]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH3:24])=[CH:14][C:13]=2[F:25])[C:10]=1N)=[O:5])[CH3:2].N(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][CH2:27][CH3:28])=[N:8][N:9]([C:12]2[CH:17]=[C:16]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH3:24])=[CH:14][C:13]=2[F:25])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)nn(-c2cc(SCC(F)(F)F)c(C)cc2F)c1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2cc(SCC(F)(F)F)c(C)cc2F)nc1OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
Then, 1.48 g of ethyl-5-amino-3-ethoxy-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole-4-carboxylate was dissolved in 50 mL of tetrahydrofuran, and 0.44 g of tert-butyl nitrite was added under cooling with ice, followed by stirring at room temperature for 12 hours. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 1.18 g of ethyl-3-ethoxy-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:6]=1[CH2:22]Br)=[O:4].[CH3:24][O:25][C:26](=[O:39])[CH2:27][NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:6]=1[CH2:22][N:28]([CH2:27][C:26]([O:25][CH3:24])=[O:39])[S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30])=[O:4]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(OC)cc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.55 g, 5.73 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (1.32 g, 5.44 mmol), sodium iodide (1.72 g, 11.5 mmol) and potassium carbonate (1.58 g, 11.5 mmol) in DMF (50 mL) was stirred at r.t. for 16 h. Brine (100 mL) was added and the mixture was extracted with EtOAc. The organic layer was washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-60% EtOAc/hexanes) to give 2.03 g of the title compound as a viscous oil. MS: (+) m/z 629.17, 631.06 (M+Na, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([N:8]1[CH:7]([CH3:20])[CH2:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:9]1)=[O:28])([CH3:25])[CH3:24]
Reactant: CC1Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2CC1C
Yield: 53 %

Procedure:
0.6 g (1.9 mmoles) of 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 5, Step D or in Example 36, starting compound) are reacted with isopropyl isocyanate according to the method of Example 44. The crude product is recrystallized from ethanol. Thus, 0.4 g (53%) of the title compound are obtained. M.p.: 172°-174° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.O.[OH-].[Li+].CO.Cl>C1COCC1.O>[CH2:17]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][N:6]=2)=[CH:16][O:15][N:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1nocc1COc1ccc(C(=O)OC)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nocc1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a suspension of 6-(3-butyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (4.0 g, 13.8 mmol) in THF (25 mL) was added a solution of lithium hydroxide monohydrate (1.2 g, 27.6 mmol) in water (25 mL) and then methanol (7 mL) added and the resulting mixture stirred at room temperature for 2 h. The mixture was acidified to pH 1 with HCl (1 N, 80 mL) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (3.9 g, 100%) which was obtained as an off white solid. MS: m/e=277.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:5][N:4]=1.[Li+].[Br-:16].CC(=O)OCC>C1COCC1>[Br:16][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:5][N:4]=1
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Reactant: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cccc(-c2nc(CBr)no2)c1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.38 g, 6.0 mmol) and LiBr (0.90 g, 10.3 mmol) in THF (50 ml) were heated to reflux under a nitrogen atm. o.n. After cooling to r.t. EA was added and the organic phase was washed with H2O and brine, dried and evaporated to give the title compound (1.40 g, 85%). MS (M++1) 275.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH2:8][CH2:9][CH:10]3O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH2:8][CH:9]=[CH:10]3)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: OC1CCc2c1cccc2-n1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=Cc2cccc(-n3cccc3)c2C1
Yield: 100.3 %

Procedure:
In the manner of Example 1, step I, heating 2.3 g (0.011 mole) of 4-(1-pyrrolyl)-1-indanol in the presence of 0.1 g of p-toluenesulfonic acid and 50 mL of toluene gave 2.0 g of 7-(1-pyrrolyl)-1H-indene as an oil.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[N:16]1([C:21]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:7][N:6]1[C:2]([C:24]2[CH:23]=[CH:22][C:21]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:26][CH:25]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(N2CCCC2)cc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(N2CCCC2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-pyrrolidinophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H19N5, 330. Found, 330.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.Cl[C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:15]=[C:14]([C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1)[N:13]=2>CN1CCCC1=O>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[N:15]=[C:14]([C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1)[N:13]=2
Reactant: CC(C)Cn1c(Cl)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CN1CCCC1=O
Product: CC(C)Cn1c(N2C[C@@H](C)NC[C@@H]2C)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 150 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
trans-2,5-Dimethylpiperazine (150 mg, 1.3 mmol) and N-methylpyrrolidone (1 ml) were added to 5-(8-chloro-9-isobutyl-6-morpholin-4-yl-9H-purin-2-yl)pyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture was stirred at 150° C. for 48 hours. The reaction mixture was cooled and partitioned with methylene chloride and water, the organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (120 mg) as a pale yellow solid.
Reaction SMILES: C(O)(C)(C)C.[OH:6][CH2:7][CH:8]([S:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.ClCCl>[O:6]=[CH:7][CH:8]([S:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(CSC(CO)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COc1ccc(CSC(C=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of t-butanol (167 mg, 1.05 eq), 1,1,1-triacetoxy-2,1-benoxiodol-3(3H)-one (954 mg, 1.05 eq) and dry methylene chloride (8 ml) was stirred under argon at room temperature for 15 minutes. The mixture was then treated with a solution of (1S)-[3-hydroxy-2-[[(4-methoxyphenyl)methyl]thio]-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (890 mg, 2.14 mmol) and dichloromethane (8 ml). After stirring for 15 minutes, the reaction was diluted with ether and poured into 1N sodium bicarbonate containing a seven-fold excess of sodium thiosulfate (3.9 g, 15.75 mmol). The mixture was stirred until all solids dissolved. The layers were separated and the organic phase washed with 1N sodium bicarbonate, water and brine. Drying over anhydrous magnesium sulfate and removal of solvent yielded the title compound as a pale yellow solid: 860 mg (2.08 mmol); Rf =0.75 (silica gel, benzene: ethyl acetate, 4:1).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>ClCCCl.C(OC(C)C)(C)C>[Cl:31][C:27]1[CH:26]=[C:25]([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH:10]3[CH:15]([CH2:16][N:8]([C:33]([O:35][CH:36]=[CH2:37])=[O:34])[CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CN(Cc3ccccc3)CC12
Reactant: C=COC(=O)Cl
Solvent: CC(C)OC(C)C
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)CCC(c3cccc(Cl)c3)(c3cccc(Cl)c3)C2C1

Procedure:
A solution of (3aRS,7aRS)-2-benzyl-7,7-bis-(3-chlorophenyl)-4-perhydroisoindolone (11.5 g) in 1,2-dichloroethane (250 cc) is treated with vinyl chloroformate (2.8 cc) and refluxed for 16 hours and then concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 6 cm, height 32 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20) and collecting 25 cc fractions. Fractions 19 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is solidified in isopropyl ether and the precipitate is drained, washed with isopropyl ether and dried to give (3aRS,7aRS)-7,7-bis-(3-chlorophenyl)-2-vinyloxycarbonyl-4-perhydroisoindolone (6.7 g) in the form of a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH3:30])([CH3:29])[O:6][C:7]3[C:12]([C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([NH:21]C(=O)OC(C)(C)C)[CH:8]=3)[CH2:3][CH2:2]1.Cl.O1CCOCC1>>[CH:1]1([C:4]2[C:5]([CH3:30])([CH3:29])[O:6][C:7]3[C:12]([C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([NH2:21])[CH:8]=3)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(C1CC1)=C2c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)Oc2cc(N)ccc2C(c2ccc(F)cc2)=C1C1CC1

Procedure:
The compound obtained in (2) described above (115 mg) and 4N hydrochloric acid-dioxane solution (4 mL) were treated in the same manner as Reference Example 5(5) to give the titled compound as a crude product (a yellow powder).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:25]([O-])=O)[N:9]=2)=[CH:4][CH:3]=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH2:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2nc(-c3ccc(Br)cc3)c(-c3ccc(Br)cc3)nc12
Solvent: C1COCCO1
Product: Nc1cccc2nc(-c3ccc(Br)cc3)c(-c3ccc(Br)cc3)nc12

Procedure:
1.01 g (2.1 mmol) of 2,3-di(4-bromophenyl)-5-nitro-quinoxaline was dissolved in 30 g of dioxane, followed by purging well with argon, adding 0.3 g of 5% Pd/C (hydrous) and purging well with argon again. This system was purged with a hydrogen gas and reacted at room temperature for 24 hours. After completion of the reaction, the system was filtered. The resulting filtration residue was washed with acetone and then with dioxane and filtered again. The solvent was removed from the resulting filtrate and a reaction product was extracted with a silica gel column.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][NH:35][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([CH:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:22][CH:21]=1
Reactant: CC(C)CC(Sc1ccc(Br)cc1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a mixture of 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid (379 mg, 1 mmol) in methylene chloride (10 mL) are added triethyl amine (0.42 mL, 3 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (209 mg, 1.5 mmol) and EDCI (577 mg, 3.0 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(4-Bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (350 mg).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:27])[CH:6]([S:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10][CH:9]=1.[CH3:30][S:31]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][CH:36]=1)(=[O:33])=[O:32].CS(O)(=O)=O>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][S:17][CH:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:43][C:42](=[O:44])[CH2:41][C:38]3[CH:37]=[CH:36][C:35]([O:34][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:40][CH:39]=3)=[CH:12][CH:13]=2)[C:5]([OH:27])=[O:4])=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Oc1ccc(CC(=O)O)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CCO)cc1)SCCc1ccc(F)cc1
Agent: CS(=O)(=O)O
Product: CS(=O)(=O)Oc1ccc(CC(=O)OCCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-[4-(2-hydroxy-ethyl)-phenyl]-propionic acid 2,2,2-trichloro-ethyl ester (34 mg, 0.072 mmol) and methanesulfonic acid (4-methanesulfonyloxy-phenyl)-acetic acid (15 mg, 0.065 mmol) in the same manner as described for example 1. The crude product was purified by HPLC (yield: 3.0 mg, 8.2%). 1H NMR (400 MHz, CDCl3): δ 7.17-7.24 (m, 4H), 7.00-7.10 (m, 6H), 6.89-6.93 (m, 2H), 4.26 (t, 2H), 3.80 (t, 2H), 3.46-3.50 (dd, 2H), 3.11 (s, 3H), 2.77-2.91 (m, 8H).