Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21].[Cl-].[NH4+]>CN(C)C=O>[Cl:21][CH2:20][CH2:19][CH2:18][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: ClCCCN1c2ccccc2Oc2ccccc21
Reaction time: 0.25 h

Procedure:
To a solution of phenoxazine (3.7 g, 0.02 mol) in dry dimethylformamide (100 ml) kept under an atmosphere of nitrogen, sodium hydride (1.2 g, 0.03 mol, 60% dispersion in oil) was carefully added. The reaction mixture was left stirring for 15 minutes. 1-Bromo-3-chloro-propane (8.0 g, 0.05 mol) was added and the mixture was left stirring overnight. Ammonium chloride (2.0 g, 0.04 mol) was added, and after continued stirring for 30 minutes, the solution was poured onto water (300 ml). The mixture was extracted with dichloromethane (2×200 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent evaporated in vacuo. 10-(3-Chloropropyl)-10H-phenoxazine was obtained in quantitative yield as an oil and used without further purification. Rf : 0.68 (SiO2 ; n-heptane/ethyl acetate=1:1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1.[O-:16][C:17]#[N:18].[Na+].C(O)(=O)C(C1C=CC=CC=1)O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:17]([NH2:18])=[O:16])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1
Reactant: N#C[O-]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: O=C(O)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
A suspension of 10 g of iminostilbene in 100 ml toluene was treated with 20.2 g of sodium cyanate and 27.5 g of mandelic acid and was heated to reflux for about 10 hrs. The reaction mixture was cooled to room temperature and charged with sodium hydroxide solution and maintained for 8 hrs. The resulting suspension was filtered, washed with water and dried to give 11 g of carbamazepine.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>CN(C)C=O.O>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: OCCCCCCCl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
17 g of 4-phenylphenol (0.1 mol) was dissolved in 120 mL of N,N-dimethylformamide (hereafter abbreviated as DMF), 15.2 g of potassium carbonate powder (0.11 mol) was added with constant stirring, and the mixture was then stirred for one hour while heating at 90° C. Subsequently, 6-chloro-1-hexanol (14.3 g, 0.11 mol) was added dropwise to the mixture, and the reaction was allowed to proceed for 12 hours under constant stirring. Following confirmation by gas chromatography that the peaks derived from the raw materials had disappeared, the reaction mixture was diluted with water, and the precipitated solid was recovered by filtration. The resulting solid was then recrystallized from ethanol, yielding 23 g of 4-(6-hydroxyhexyloxy)phenylbenzene (yield: 85%).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](Cl)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([N:8]2[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Yield: 127.3 %

Procedure:
The procedure described in Example 17, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of triethylamine and 0.8 g of 3,4-dichlorophenylacetyl chloride, to afford 1.01 g of the title compound, melting at 223°-227° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:3]1.[OH-].[Na+]>C(O)(=O)C.[Zn]>[CH3:1][NH:2][CH2:6][CH2:5][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3]
Reactant: CN1CCC(c2ccccc2)O1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CNCCC(O)c1ccccc1

Procedure:
2-Methyl-5-phenylisoxazolidine (2.0 g, 12.3 mmol) and Zn powder (1.2 g, 18.3 mmol) in 10 molar aqueous acetic acid are heated to 65-70° C. for 4 hours. Additional Zn powder (0.4 g, 6.1 mmol) is added and heating is continued for one more hour. The reaction mixture is neutralized with sodium hydroxide and extracted with chloroform. The extract is dried (K2CO3) and concentrated to give N-methyl-3-phenyl-3-hydroxypropyl-amine.
Reaction SMILES: C(O)=O.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@:12]12[CH2:20][O:19][C@H:18]([CH2:21][O:22]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:17]1[CH2:16][S:15][C:14]([NH:42][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[N:13]2.C(N(CC)CC)C>O>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@:12]12[CH2:20][O:19][C@H:18]([CH2:21][OH:22])[C@H:17]1[CH2:16][S:15][C:14]([NH:42][C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[N:13]2
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Solvent: O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Reaction time: 0.42 h
Yield: 101.8 %

Procedure:
Formic acid (116 mL) was added to N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (33.30 g, 0.051 mol, 1.0 equiv.), the mixture was stirred at r.t for 25 min. Water (17 mL) was added dropwise then the reaction was stirred for another 30 min. The resulting suspension was filtered; the filtrate was dried by azeotropic distillation under vacuum with toluene (360 mL). Methanol (110 mL) was added followed by triethylamine (22 mL, 0.15 mol, 3.0 equiv.) and the solution was stirred for 2 h. The solvent was removed under vacuum and chased with toluene (66 mL). The residual oil was dissolved in CH2Cl2 (250 ml) and washed successively with aq.HCl (1M, 100 mL), sat aq.NaHCO3 (67 mL) and 18% aq.NaCl (67 mL). The organic phase was concentrated under reduce pressure. Toluene (66 mL) and THF (67 mL) were added to the residue then the solution was filtered through celite and concentrated under reduced pressure to yield the title compound (21 g). 1H NMR (500 MHz, DMSO) ppm 8.11 (dd, J=16.4, 4.2 Hz, 2H), 7.70-7.58 (m, 1H), 7.57-7.44 (m, 3H), 7.43-7.34 (m, 1H), 7.34-7.26 (m, 1H), 4.43 (d, J=9.5 Hz, 1H), 4.25-4.16 (m, 1H), 4.10 (d, J=9.2 Hz, 1H), 3.59 (d, J=4.5 Hz, 2H), 3.30-3.21 (m, 1H), 3.20-3.08 (m, 2H); 13C NMR (125 MHz, DMSO) δ ppm 169.08, 150.95 (dd, JCF=245.8, 13.1 Hz), 148.22, 148.09 (dd, JCF=248.7, 13.2 Hz), 133.46, 129.11, 128.99, 128.62, 125.43, 124.70, 118.16 (d, JCF=16.9 Hz), 81.36, 75.29, 66.76, 62.39, 40.77, 24.25.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([C:14]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([O:30]CC)=[O:29])[CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1.Cl>CO.C(OCC)(=O)C>[C:28]([C:24]1[CH:23]=[C:22]([CH2:21][S:20][C:15]2[C:14]([C:12]([NH:11][C:6]3[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[CH:5]=3)=[O:13])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:27]=[CH:26][N:25]=1)([OH:30])=[O:29]
Reactant: CCOC(=O)c1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(C(=O)O)c2)c1
Yield: 84 %

Procedure:
A 1N aqueous sodium hydroxide solution (0.5 mL) was added to a solution of N-(3,5-dimethylphenyl)-2-(2-ethoxycarbonylpyridin-4-ylmethylthio)pyridine-3-carboxamide (95 mg, 0.22 mmol, Compound No. 1-241) in methanol (2 mL), then the mixture was stirred at room temperature for 1.5 hours. 1N hydrochloric acid (1 mL) was added to the reaction mixture, and this mixture was diluted with ethyl acetate (35 mL). The mixture was washed with brine (20 mL), and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the resulting residue was filtered off. The solid was washed with diethyl ether, and then dried at 50° C. under reduced pressure to give 74 mg of the target compound as an orange solid. (Yield 84%)
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=[O:13].[BH4-].[Na+].[Cl-].[Na+]>CO>[CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][OH:13]
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccnc1CO

Procedure:
To 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-2-carboxaldehyde (prepared according to the procedure of Whitten, Matthews and McCarthy, J. Org. Chem., 1986, 51, 1891) (7.45 g) in methanol (30 ml) was added sodium borohydride (0.42 g) at 0° C. with stirring. The solution was stirred at 0° C. for 40 min. Saturated sodium chloride solution (15 ml) was added, and the mixture stirred at room temperature for 15 min. The methanol was removed in vacuo, and the resultant aqueous solution was washed with ethyl acetate (3×50 ml). The organic layers were combined, dried (sodium sulfate) and concentrated in vacuo to yield an oil, which crystallised at 0° C. The solid was washed and recrystallised from hexane to yield 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-(hydroxymethyl)imidazole as colourless crystals (1.99 g). 1H NMR (250 MHz, CDCl3) δ 0.00 (9H, s), 0.93 (2H, t, J=8.2 Hz), 3.54 (2H, t, J=8.2 Hz), 4.73 (2H, s), 4.77 (2H, br s), 5.39 (2H, s), 6.94 (1H, d, J=1.4 Hz), 7.00 (1H, d, J=1.4 Hz); MS (ES+) m/e 229 [MH]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]>CC(N(C)C)=O>[CH3:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH3:21])=[CH:9][N:8]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Sodium hydride (25.6 g, 60% dispersion in oil, 0.64 mol) was added portion wise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while keeping the temperature below 40° C. At the end of the addition, the mixture was stirred at room temperature for 1 hour and 2-fluoro-5-nitrotoluene (91.3 g, 0.59 mol) in DMA (100 ml) was added slowly. The mixture was stirred at 80° C. for 3 hours and then cooled. The solvents were evaporated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer washed with water and brine, dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 30% ethyl acetate in petroleum ether) to give 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 98%) as an oil; NMR spectrum (CDCl3); 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, 1H), 7.21 (d, 1H), 7.27 (d, 1H), 8.00 (d, 1H), 8.17 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[O:10]1[CH:14]=[CH:13][CH2:12][C:11]1=O>C1(C=CC(O)=CC=1)O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:10])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1CC=CO1
Agent: Oc1ccc(O)cc1
Product: O=C1CCCN1Cc1ccc(F)cc1
Yield: 74.8 %

Procedure:
47 g (0.376 mol) of p-fluorobenzylamine, 30.4 g (0.353 mol) of furan-2-one and 0.4 g of hydroquinone are introduced into a 125 ml autoclave. After driving the air out of the apparatus by passing a stream of nitrogen through it, the mixture is heated to 250° for 6 hours. It is then cooled and distilled under reduced pressure. 51 g (yield=74.8%) of 1-p-fluorobenzyl-pyrrolidin-2-one are collected as a colourless liquid distilling at 103°-105° under a pressure of 0.01 mm of mercury and solidifying slowly. Melting point=37°-38°.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1>CN(C=O)C.CC(=O)OCC>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:5][CH2:4][CH:2]2[CH2:3][CH2:1]2)=[N:13][CH:14]=1
Reactant: OCC1CC1
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-cyclopropyl-methanol (6.15 g) and DMF (12 mL) was added NaH (60% in mineral oil, 1.5 g) at 0° C. After stirring for 4 hours at r.t. the mixture was diluted with DMF (5 mL) and 5-bromo-2-fluoro-pyridine (6.00 g) was slowly added keeping the reaction temperature below 30° C. After 30 minutes at r.t. the mixture was heated to 130° C. for 1 hour by microwave irradiation. After cooling to r.t. the mixture was diluted with EA and washed with water (3 times). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by SGC to provide the subtitle compound. MS ESI+: m/z=228 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:8]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:7][N:6]=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])([O-:26])=[O:25].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CC(N(C)C)=O.C(OCC)(=O)C>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:8]([C:19]3[NH:23][CH:22]=[CH:21][N:20]=3)=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)=[O:31])[N:10]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: N#Cc1ccc(-c2nc(NCCN)ncc2-c2ncc[nH]2)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(-c2nc(NCCNC(=O)c3cccc([N+](=O)[O-])c3)ncc2-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
A mixture of 4-{2-[(2-aminoethyl)amino]-5-imidazolylpyrimidin-4-yl}benzene-carbonitrile (30 mg, 0.098 mmol), 3-nitrobenzoic acid (17 mg, 0.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (19 mg, 0.1 mmol), 1-bydroxybenzotriazole hydrate (HOBT) (14 mg, 0.1 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in DMA (500 uL) were stirred at room temperature. After 12 hours, the reaction was diluted with ethyl acetate (10 ml) and extracted with sat. aq. NaHCO3 (2×5 ml), water (3×5 ml), brine (5 ml), dried with Na2SO4, filtered, and concentrated. The resulting product, N-(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)(3-nitrophenyl)carboxamide weighing 32 mg (70% yield) was approximately 95% pure by LCMS and HPLC.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([Br:32])=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:34][O:35][C:36]([NH:38][CH:39]([CH:43]([CH3:45])[CH3:44])[C:40](O)=[O:41])=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.O1CCOCC1>[CH3:34][O:35][C:36](=[O:37])[NH:38][CH:39]([C:40]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([Br:32])=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:41])[CH:43]([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(Br)ccc2-3)[nH]1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(Br)ccc2-3)[nH]1)C(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a solution of 2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (187 mg, 0.38 mmol) in methanol (5 mL) was added 4.0 M solution of HCl in dioxane (2 mL, excess). The mixture was stirred for 3 hours at 50° C. and concentrated under reduced pressure. The residue was treated with ether to remove excess HCl. The obtained white solid was dissolved in DMF (5 mL), to the solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (70 mg, 0.40 mmol), HATU (173 mg, 0.46 mmol) and N,N-diisopropylethylamine (0.66 mL, 3.8 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with 1 N NaOH solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (1-{2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as an oil (200 mg, 95%). m/z 551.2, 553.2 (M+H)+.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[C:10]([N+:15]([O-])=O)=[C:9]([NH:18][CH3:19])[CH:8]=1.[OH-].[NH4+]>C(O)C>[NH2:15][C:10]1[C:11]([C:13]#[N:14])=[N:12][C:7]([Cl:6])=[CH:8][C:9]=1[NH:18][CH3:19]
Reactant: CNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1cc(Cl)nc(C#N)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
Tin(II) chloride dihydrate (21 g) was added to a suspension of 6-chloro-4-methylamino-3-nitro-pyridine-2-carbonitrile (6.6 g) in ethanol (150 ml). The mixture was stirred at room temperature for 3 hours. To above red-brown coloured solution was then added ethyl actetate (1000 ml) and followed by 10% aqueous ammonium hydroxide (200 ml). The organic layer were separated, the sticky solid pad was washed with ethyl acetate (5×200 ml). Combined organic layer was then washed with saturated sodium chloride aqueous solution (2×200 ml), dried over sodium sulphate, solvent removed to give a brown solid as expected product (5.7 g). 1H NMR (CD3OD) δ: 6.45 (s, 1H), 2.89 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][CH:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:12][N:11]=1)=[O:9])C.FC(F)(F)C1C=CC(C2N=CC(C=O)=CN=2)=CC=1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:20][CH:19]([CH3:21])[CH2:18][CH:17]([NH:16][C:13]1[CH:12]=[N:11][C:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:9])=[N:15][CH:14]=1)[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCNC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Agent: Cl
Agent: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(Nc1cnc(C(=O)NCCC(=O)O)nc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
3-({5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester Peak 2 (150 mg, 0.284 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (1 mL), and 1.0 M NaOH (1 mL) was added. This was stirred at room temperature for 10 min. The reaction brought to pH 4 with 1 N HCl. This was extracted twice with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give an oil. The material was triturated with four portions of diethylether to give the opposite enantiomer of 3-({5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid (111 mg, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6, δ): 12.21 (br. s., 1H) 8.39 (t, J=6.0 Hz, 1H) 8.16 (s, 2H) 7.83-7.91 (m, 2H) 7.75-7.81 (m, 2H) 7.70 (d, J=8.2 Hz, 2H) 7.54 (d, J=8.2 Hz, 2H) 7.27 (d, J=7.6 Hz, 1H) 4.61-4.72 (m, 1H) 3.36-3.45 (m, 2H) 2.44 (t, J=6.9 Hz, 2H) 1.74-1.85 (m, 1H) 1.62-1.72 (m, 1H) 1.50-1.61 (m, 1H) 0.98 (d, J=6.4 Hz, 3H) 0.92 (d, J=6.4 Hz, 3H); MS (M+1): 501.6.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][CH2:24][C@@H:25]([NH2:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(=O)OCC.CN(C=O)C>[CH3:22][O:23][CH2:24][C@@H:25]([NH:27][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:26]
Reactant: COC[C@H](C)N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12

Procedure:
To a mixture of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2.0 g, 5.37 mmol), (S)-1-methoxypropan-2-amine (718 mg, 8.06 mmol), and HATU (4.09 g, 10.7 mmol) were added DMF (20 mL) and DIPEA (3.75 mL, 21.5 mmol) at room temperature under nitrogen atmosphere. The resulting solution was stirred for 15 h at room temperature at which time LCMS analysis and TLC (1:1, Hex:EA, Rf=0.4) system indicated the presence of the desired compound. The reaction was diluted with water (−100 mL), the organic compound was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with brine solution. After drying over MgSO4, the filtrate was concentrated to obtain the crude light brown solid (−4.1 g) which was purified by chromatography using an ISCO (120 g) column eluting with hexanes (1 min), 0-30% EA in hexanes (2 min), 30-60% EA in hexanes (15 min) to obtain 1.9 g (80%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:19])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>CC(CC)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:26][CH:28]2[O:30][CH2:29]2)=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC1CO1
Yield: 57.8 %

Procedure:
Methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate (0.75 g, 0.0028 mole), anhydrous potassium carbonate (0.39 g, 0.0028 mole), epibromohydrin (0.78 g, 0.00565 mole) and dry ethyl methyl ketone (20 ml) were stirred and heated under reflux for 16 hours. The cooled mixture was filtered and evaporated under reduced pressure to an oil which was purified by elution from a silica column with chloroformmethanol to give methyl 3-[5-acetamido-2-(2,3-epoxypropoxy)benzoyl]propionate (0.52 g, 57%, m.p. 84°-87°).