Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.N#N.[CH:25]1([C:28]#[CH:29])[CH2:27][CH2:26]1.[CH2:30](N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu](I)I.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>[CH:25]1([C:28]#[C:29][C:2]2[S:3][CH:4]=[C:5]([CH:7]([O:8][N:9]=[C:10]([C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:30])[N:6]=2)[CH2:27][CH2:26]1
Reactant: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: C#CC1CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(ON=C(c1ccccc1)c1nnnn1C)c1csc(C#CC2CC2)n1
Reaction time: 0.05 h
Yield: 51.5 %

Procedure:
To a stirred solution of N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.15 g, 0.38 mmol, 1 eq.) in 2 ml dry THF “degassed” with N2, was added Cyclopropylacetylene (70%, 0.144 g, 1.52 mmol, 4 eq.) followed by N-ethyldiisopropylamine (0.256 g, 1.98 mmol, 5.2 eq.), Copper Iodide (0.022 g, 0.1141 mmol, 0.3 eq.) and Tetrakis(triphenylphosphine)palladium (0.132 g, 0.114 mmol, 0.2 eq.). The reaction was microwaved 120° C./normal/fixed hold/pre stir 100 s for 180 s. The reaction was diluted with EtOAc and filtered through a “celite” plug. The solvent was evaporated and the residue was purified by chromatography on silica gel to give N-{1-[2-(cyclopropylethynyl)-1,3-thiazol-4-yl]ethoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.074 g, 48% yield) as a yellow viscous oil.
Reaction SMILES: C(OC(=O)C)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:19]1[CH2:23][CH2:22][O:21][CH2:20]1.C([N:27](C(=O)C)[C:28]1[NH:29][C:30](=[O:37])[C:31]2[NH:32][CH:33]=[N:34][C:35]=2[N:36]=1)(=O)C>C1(C)C=CC=CC=1>[OH:19][CH2:23][CH2:22][O:21][CH2:20][N:34]1[CH:33]=[N:32][C:31]2[C:30](=[O:37])[NH:29][C:28]([NH2:27])=[N:36][C:35]1=2
Reactant: C1COCO1
Reactant: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To a mixture of acetic anhydride (1.2 ml) and p-toluenesulfonic acid (0.09 g) was added with stirring dioxolane (1.02 g)-caution, exothermic. The solution was allowed to cool for several minutes. Diacetylguanine (1.45 g) and dry toluene (9 ml) were added and the reaction mixture was stirred at reflux for 18 hr. and then allowed to cool to room temperature. The toluene was decanted off and the residue triturated several times with benzene. Methanol (10 ml) was added to the residue and evaporated under reduced pressure. To the residue was added 40% aqueous methylamine (10 ml) and the mixture heated on a steam bath for 20 min. The water and methylamine were removed under reduced pressure, ethanol (10 ml) was added and evaporated. The residue was thoroughly extracted with boiling methanol (700 ml total) and the combined extracts evaporated. The resulting solid was triturated with cold ethanol and then recrystallized from methanol to give 9-(2-hydroxyethoxymethyl)guanine (0.3 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:7]=1[CH2:33][C:34]([O:36]CC)=[O:35])=[O:5])C.[OH-].[Na+].O1CCOCC1.Cl>O>[C:34]([CH2:33][C:7]1[N:8]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][C:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)=[CH:11][CH:10]=2)([OH:36])=[O:35]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1c(C(=O)O)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 1-(4-chlorophenyl)-2-ethoxycarbonylmethyl-5-(4-trifluoromethylphenoxy)indole-3-carboxylic acid ethyl ester (140 mg, 0.25 mmol, see step (c) Example 2), NaOH (aq, 2M, 2 mL) and dioxane (2 mL) were heated at 120° C. for 4.5 h, cooled, diluted with H2O, acidified to pH 2 with HCl (aq, 1 M) and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was treated with CH2Cl2 (2 mL) to give the title compound as a white solid which was recrystallised from CH2Cl2/EtOH (9:1). Yield 45 mg (37%), mp 974-276° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH2:35])(=[O:34])=[O:33]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:35][S:32]([CH2:31][CH2:30][CH2:29][Cl:28])(=[O:34])=[O:33])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)CCCCl
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CCCCl)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-chloropropanesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method A described hereinabove. Yield (80%); 1H NMR (d6-DMSO) δ 11.82 (br s, 1H), 7.48 (d, J=15.7 Hz, 1H), 7.40-7.09 (m, 12H), 6.87 (d, J=8.4 Hz, 2H), 6.46 (d, J=15.7 Hz, 1H), 3.71 (t, 2H), 3.52 (t, 2H), 2.37 (q, J=7.3 Hz, 2H), 2.07 (p, 2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 492 (M−H−).
Reaction SMILES: [C:1]1([CH2:7][C:8](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:22][C:23]1[C:28]([CH:29]=O)=[CH:27][N:26]=[C:25]([S:31][CH3:32])[N:24]=1.P(Cl)(Cl)([Cl:35])=O>C1COCC1>[Cl:35][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:29][C:28]2[CH:27]=[N:26][C:25]([S:31][CH3:32])=[N:24][C:23]=2[N:22]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc2cc(-c3ccccc3)c(Cl)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of methyl phenylacetate (0.945 g, 6.29 mmol) in THF (20 mL) at −78° C. was added LHMDS (1 M, 6.6 mL) and stirred for 1 h. 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (1-2; 0.507 g, 3.0 mmol) was added. The mixture was stirred and warmed to rt. The reaction was quenched with saturated NH4Cl solution and extracted with CH2Cl2. The combined organic layer was dried, filtered and concentrated. The residue was dissolved in CH3CN (5 mL) and phosphorus oxychloride (4.6, 30 mmol) was added. The mixture was heated to reflux overnight. After cooled to rt, the reaction mixture was concentrated. The residue was basified with saturated NaHCO3 solution and extracted with CH2Cl2. The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (0.5% MeOH in CH2Cl2) to give the title compound (1-3). LRMS m/z (M+H) Calcd: 288.7, found: 288.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[CH:7][CH2:6][CH2:5]2.[OH2:20].[Br:21]NC(=O)C>CC(C)=O>[Br:21][CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[C:8]1([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[OH:20]
Reactant: Clc1ccc(C2=CCCc3cc(Cl)c(Cl)cc32)cc1
Reactant: CC(=O)NBr
Reactant: O
Solvent: CC(C)=O
Product: OC1(c2ccc(Cl)cc2)c2cc(Cl)c(Cl)cc2CCC1Br
Reaction time: 2 h

Procedure:
6,7-Dichloro-1-(4-chlorophenyl)-3,4-dihydronaphthalene (3.0 g.) was dissolved in acetone (80 ml.), then water (30 ml.) was added, followed by a solution of N-bromoacetamide (3.0 g.) in acetone (40 ml.), and the mixture was stirred for 2 hours. The reaction mixture was then poured into water (150 ml.) and extracted with ether (3×80 ml.), the extracts were combined and dried, and the solvent was evaporated under reduced pressure to leave an oil. This residual oil was chromatographed on silica (Merck's Grade 7734), using 30% by volume of diethyl ether in petroleum ether (b.p. 60°-80° C.) as the eluant, to give the required 2-bromo-6,7-dichloro-1-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthol, m.p. 103°-104.5° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[N:16]=[C:15](Cl)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]>O1CCCC1>[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][NH:35][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[C:7]([Cl:6])[N:16]=3)=[CH:32][CH:33]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(CNc2nc(Cl)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium acetate (0.65 g), 2,4-dichloroquinazoline (0.52 g) and 4'-aminomethyl[1,1'-biphenyl]-2-carboxylic acid methyl ester (0.73 g) were suspended in 25 mL of tetrahydrofuran. The reaction was stirred at room temperature for approximately 18 hours at which time the solvents were evaporated. The residue was loaded onto a silica gel column and the desired product was eluted with ethyl acetate/hexane (1:1). The yield was 0.75 g (71%) (m.p.=75°-90° C.): 1H NMR (DMSO-d6, 300 MHz) δ 9.30 (t, J=6 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.81 (m, 1H), 7.71 (m, 1H), 7.60 (m, 3H), 7.45 (m, 4H), 7.25 (d, J=8.1 Hz, 2H), 4.80 (d, J=5.8 Hz, 2H), 3.58 (s, 3H); positive FAB MS m/e 404(MH). Anal. calcd for C23H18ClN3O2 : C, 68.40; H, 4.49; N,10.40. Found: C,68.09; H, 4.57; N, 10.10.
Reaction SMILES: I[C:2]1[C:10]2[O:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]=2[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][CH:27]=1)#[CH:21]>>[C:31]([O:30][C:29]([NH:28][C:24]1[CH:23]=[C:22]([C:20]#[C:21][C:2]2[C:10]3[O:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]=3[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=2)[CH:27]=[CH:26][CH:25]=1)=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)Cn1c(=O)oc2c(I)cc([N+](=O)[O-])cc21
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Product: COC(=O)Cn1c(=O)oc2c(C#Cc3cccc(NC(=O)OC(C)(C)C)c3)cc([N+](=O)[O-])cc21

Procedure:
The desired compound was prepared according to the procedure of Example B5, step C, using methyl (7-iodo-5-nitro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate and tert-butyl (3-ethynylphenyl)carbamate as the starting materials in quantitative yield. LCMS for C23H21N3O8Na (M+Na)+: m/z=490.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[N-:9]=[N+:10]=[N-:11].[Na+].O>CC(C)=O>[N:9]([CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1)=[N+:10]=[N-:11]
Reactant: Cc1cc(CBr)no1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(CN=[N+]=[N-])no1
Reaction time: 48 h

Procedure:
To a solution of the 3-bromomethyl-5-methyl-isoxazole in acetone is added NaN3 at rt. The reaction mixture is then stirred for about 48 h. Then, the reaction mixture is poured into water and extracted with EtOAc, dried and evaporated.
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].Br[CH2:9][C:10]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]2[C:11]=1[N:12]=[C:13]([O:23][CH3:24])[C:14]([O:21][CH3:22])=[N:15]2.O>CO>[Br:20][C:18]1[CH:17]=[C:16]2[C:11]([N:12]=[C:13]([O:23][CH3:24])[C:14]([O:21][CH3:22])=[N:15]2)=[C:10]([CH:9]=[O:3])[CH:19]=1
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1nc2cc(Br)cc(C=O)c2nc1OC
Reaction time: 1 h

Procedure:
1.38 g (60 mmol) of sodium are dissolved in portions, at 0° C. under N2, in 200 ml of methanol. At 0° C., 5.85 ml (65 mmol) of 2-nitropropane are added dropwise. 18.1 g (50 mmol) of 5-(bromomethyl)-7-bromo-2,3-dimethoxy-quinoxaline are then added. The beige suspension is heated to reflux and stirred for 1 hour. The reaction mixture is poured onto 600 ml of water and the methanol is distilled off. The residue is extracted twice with ethyl acetate, and the organic phases are dried over sodium sulfate and filtered with suction. The filtrate is concentrated and the residue is dried under a high vacuum. 7-Bromo-5-formyl-2,3-dimethoxy-quinoxaline is obtained in the form of beige crystals having a melting point of 179-182° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[S-2].[Na+].[Na+]>>[CH3:4][CH:2]1[O:3][C:1](=[O:5])[CH:2]([CH3:4])[O:6][C:1]1=[O:5]
Reactant: CC(O)C(=O)O
Agent: [Na+]
Agent: [S-2]
Product: CC1OC(=O)C(C)OC1=O

Procedure:
100 g of the thus obtained residue is heated with 50 g hydrolysis medium (90% lactic acid in aqueous solution) at 100° C. and atmospheric pressure for 4 hours with reflux and continuous thorough mixing. The resulting solution is mixed with sodium sulphide and, after 30 min thorough mixing, is filtered in order to remove solid material particles. The thus obtained, homogeneous solution has a lactic acid proportion of over 99% by weight and a racemisation degree of 2.5% and can be mixed with polycondensate in order to supply it directly to the depolymerisation unit. The total racemisation degree of the dilactide obtained after a plurality of cycles never rises, despite the recycling, above the maximum value which is achieved during direct depolymerisation up to a conversion of 95% (see example 1). The total yield is determined by the quantity which is removed during the hydrolysis by separation of the impurities and is preferably above 99%, however in any case more than 95%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9]O)=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:13][CH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: ClCc1cnc(Cl)c(Cl)c1

Procedure:
2,3-Dichloro-5-hydroxymethyl-pyridine is reacted in a known manner with thionyl chloride to give 5-chloromethyl-2,3-dichloro-pyridine and the latter is reacted with sodium cyanide, without additional purification (for example analogously to L. A. Carlson et al., Acta Pharm. Suecica 9, 411 (1972)). 5,6-Dichloro-pyridine-3-acetonitrile, thus obtained, melts at 72°-75° C. after recrystallisation from ether.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: O=C(CCCCl)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CCCC(=O)c2ccccc2)CC1

Procedure:
A mixture of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (4) (100 mg, 0.4 mmol), 4-chloro-1-phenylbutan-1-one (12) (100 mg, 0.55 mmol), and triethylamine (0.4 mL) in ethanol (3 mL) was heated at reflux for 16 hours. Ethanol was removed under reduced pressure and the residue was purified by preparative TLC using 10% methanol in dichloromethane as mobile phase to afford N-(2,6-dimethylphenyl)-2-[4-(4-oxo-4-phenylbutyl)piperazin-1-yl]acetamide, a compound of formula (16).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[N:8][C:7]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][OH:27])=[CH:6][N:5]=1)(O)=[O:2].[NH2:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][N:32]([CH3:36])[CH2:31]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:36][N:32]1[CH2:33][CH2:34][O:35][CH:30]([CH2:29][NH:28][C:1]([C:4]2[C:9]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=3)=[N:8][C:7]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][OH:27])=[CH:6][N:5]=2)=[O:2])[CH2:31]1
Reactant: CN1CCOC(CN)C1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)cnc2C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)cnc2C(=O)NCC2CN(C)CCO2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A mixture of (S)-2-carboxy-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine (80 mg) obtained in Example 22 (5), 2-aminomethyl-4-methylmorpholine (31.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (43 mg), 1-hydroxybenzotriazole (30.3 mg) in N,N-dimethylformamide (3 ml) is stirred at room temperature for 18 hours. To the reaction mixture is poured water, and the mixture is extracted with ethyl acetate. The extract is washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel flesh column chromatography (solvent; ethyl acetate) to give (S)-2-[N-(4-methyl-2-morpholinyl)methylcarbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine (80.5 mg), MS (m/z): 505 (MH+), IR (Nujol): 3295, 1635 cm−1.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li:13])CCC>>[Li:13][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: C#Cc1ccccc1
Product: [Li]C#Cc1ccccc1

Procedure:
Phenylacetylene is reacted with one equivalent of butyllithium at -78° C. to give lithiophenylacetylene. Two equivalents of lithiophenylacetylene are reacted with 1,7-bis(chlorotetramethyldisiloxyl)-m-carborane to give 1,7-bis(phenylacetylenetetramethyldisiloxyl)-m-carborane. This latter material can be used in the hydrosilation reaction as 1,7-bis(ethynyltetramethyldisiloxyl)-m-carborane above.
Reaction SMILES: [C:1]1(=[CH:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:10]([CH3:13])([O-:12])=[O:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N+:10]([CH2:13][C:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: N#CC=C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC1(C[N+](=O)[O-])CCCCC1
Yield: 70.7 %

Procedure:
The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Br:19]Br>C(O)(=O)C.Br.C(O)(=O)C.CCOCC>[Br:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: BrBr
Reactant: CSc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)C(Br)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a stirred suspension of 2-(4-bromophenyl)-1-(4-methylthiophenyl)ethanone from step1 (8.4 g, 0.024 mol) in acetic acid (130 mL), bromine (3.8 g, 0.024 mol) in 25% hydrogen bromide-acetic acid solution (50 mL) was added dropwise at room temperature. After stirring for 4 h at room temperature, concentrated gave the yellow solid. The solid was suspended in ether and collected by filtration, washed with ether to give the title compound (7.5 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][C:7]#[N:8].C(O)(=O)C.[N:17]([O-])=O.[Na+].[CH3:21][O:22][C:23](=[O:29])[CH:24]([Cl:28])C(C)=O>Cl.O>[Cl:28][C:24](=[N:17][NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][C:7]#[N:8])[C:23]([O:22][CH3:21])=[O:29]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: N#CCCOc1ccccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(Cl)=NNc1ccccc1OCCC#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To aniline 84 (1.65 g, 10.2 mmol) in acetic acid (6.80 mL, 120 mmol) and 2 M of Hydrogen chloride in water (13.59 mL), then sodium nitrite (1.0290 g, 14.914 mmol;) was added while stirring vigorously at 0° C. (FIG. 18). After 20 minutes, 2-chloroacetoacetate methyl ester (1.5317 g, 10.173 mmol) was added dropwise via syringe and the mixture was warmed to room temperature over 5 hours. Then, the organic layer was extracted twice with 100 mL diethyl ether and dried with sodium sulfate, and concentrated. The crude product 85 was taken forward for next step. LRMS m/z Calcd. for C12H12ClN3O3 : 281.05672, found: 282.1 [M+1].
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)[C:13]([O-:15])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:36]=[N:37][C:38](I)=[N:39][CH:40]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.C1COCC1.O>[Br:34][C:35]1[CH:36]=[N:37][C:38]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C@H:12]([NH:11][C:9](=[O:10])[C:8]3[CH:32]=[CH:33][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=3)[C:13]([O:15][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14])=[CH:22][CH:21]=2)=[N:39][CH:40]=1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)[O-])cc1
Reactant: Brc1cnc(I)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 110 °C
Yield: 58 %

Procedure:
Prepared using General Procedure 10. Into a degassed solution of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-13 (1.0 g, 2.0 mmol), Na2HCO3 (420 mg, 3.9 mmol), and 5-bromo-2-iodopyrimidine (615 mg, 2.2 mmol) in 2/2/1 MeCN/THF/H2O was added Pd(dppf)Cl2 (140 mg, 0.2 mmol). The reaction mixture was heated at 110° C. for 1 h in a microwave reactor. The reaction mixture was concentrated, dissolved in DCM and washed with H2O. The organic layer was dried over Na2SO4, concentrated, and purified by chromatography (EA/hexanes) to provide 630 mg (58%) of tert-butyl (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate INT-14. LCMS-ESI (m/z) calculated for C28H32BrN4O3: 538.5; no m/z observed, tR=4.66 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.84-8.78 (s, 2H), 8.31 (t, J=7.0 Hz, 2H), 7.75-7.64 (m, 2H), 7.46-7.38 (m, 2H), 7.30 (dd, J=12.9, 7.1 Hz, 2H), 6.65 (d, J=7.2 Hz, 1H), 5.10-4.94 (m, 1H), 3.43-3.20 (m, 2H), 1.45 (s, 9H), 1.32 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.Cl.[N:9](OCC)=[O:10]>CCO>[N:5]1[CH:6]=[CH:7][C:2]([CH:1]=[N:9][OH:10])=[N:3][CH:4]=1
Reactant: Cc1ccncn1
Reactant: CCON=O
Agent: Cl
Solvent: CCO
Product: ON=Cc1ccncn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
9.14 g (97.11 mmol) of 4-methylpyrimidine was slowly added to a 0° C. solution of 8.75 g HCl in 40 ml EtOH. To this white suspension was added, over 5 min, 61 ml of a 10-20% by weight solution of ethyl nitrite in EtOH. The reaction was stirred at 0° C. for 10 min and then at RT for 2.5 h. The white salt was filtered and dried under vacuum. The salt was dissolved into 20 ml H2O and very slowly treated with about 200 ml saturated aqueous KHCO3. A white solid precipitated out of the purple solution. The solid was filtered and dried under vacuum to yield the titled compound.