Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7]C(O)=O.[OH-].[K+].CC1NC=CN=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH2:7]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: Cc1ncc[nH]1
Agent: [K+]
Agent: [OH-]
Product: C=Cc1ccc(OC)c(OC)c1

Procedure:
A mixture of 3,4-dimethoxycinnamic acid (0.0083 mol), KOH (10%, 5 ml), methylimidazole (1 mL) and polyethylene glycol (5 ml) were taken in a 100 ml round bottom flask fitted with reflux condenser. The flask was placed inside the microwave oven and irradiated (200 W, 200° C.) for 15 minutes. After completion of reaction, it was worked up and purified as in example V and provided a solid (m.p. 110-114° C.); 1H NMR (CDCl3) δ 7.01 (2H, m), 6.84 (1H, d, J=7.27 Hz), 6.63 (1H, d, J=10.80 Hz and J=16.10 Hz), 5.60 (1H, d, J=16.10 Hz), 5.15 (1H, d, J=10.80 Hz), 3.90 (1H, s), 3.87 (1H, s); 13C NMR (CDCl3) δ 150.1, 149.2, 137.4, 131.2, 119.8, 112.6, 111.6, 109.7 and 55.8.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][N:7]1C(OC(C)(C)C)=O.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][NH:7]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1COc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: F[C@@H]1CN[C@@H](COc2ccccc2Cl)C1

Procedure:
7.7 2.5 g of tert-butyl (2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine-1-carboxylate are dissolved in 20 ml of THF and stirred at 80° C. for 2 h with 5 ml of ethanolic hydrochloric acid. After basic work-up using saturated sodium hydrogencarbonate solution, the organic phase is subjected to conventional work-up, and the residue obtained is purified by chromatography, giving 780 mg of (2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine as brown oil; Rt.: 0.700 min; [M+H]+230.2.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4]1.[H-].[Na+].[C:15]1([C:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29]Br)[CH2:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>CN(C)C=O.C(Cl)Cl.C(C(C)=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[CH3:1][NH:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:29][CH2:28][CH2:27][N:24]1[CH2:23][CH:22]=[C:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:26][CH2:25]1
Reactant: CNC1NC(=O)c2ccccc21
Reactant: BrCCCN1CC=C(c2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of 3-methylamino-1-isoindolinone (6.8 g) in anhydrous dimethylformamide (200 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (2.2 g) in anhydrous dimethylformamide (100 cc) at a temperature close to 20° C. in the course of 15 minutes and agitation is continued for 1 hour. Then, a solution of 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-1-bromopropane (13 g) in dimethylformamide (100 cc) is added in the course of 10 minutes, and agitation is continued for a further 20 hours. The solution obtained is evaporated to dryness under reduced pressure (1 mm Hg; 0.1 kPa). The residue obtained is dissolved in methylene chloride (500 cc) and washed with distilled water (3×500 cc). The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (20 cc) and poured onto silica (750 g ) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (92-8 by volume). The first 3750 cc are eliminated and the eluate corresponding to the next 600 cc is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is dissolved in methyl ethyl ketone (50 cc). A solution of oxalic acid (1.2 g) in methyl ethyl ketone (20 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 5 g of 3-methylamino-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 122° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:15]1[O:19][C:18]([C:20]2[C:25]([NH:26]C(=O)OC(C)(C)C)=[CH:24][C:23]([C:34]([F:37])([F:36])[F:35])=[C:22]([O:38][CH3:39])[N:21]=2)=[N:17][N:16]=1)([CH3:14])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:15]1[O:19][C:18]([C:20]2[C:25]([NH2:26])=[CH:24][C:23]([C:34]([F:37])([F:36])[F:35])=[C:22]([O:38][CH3:39])[N:21]=2)=[N:17][N:16]=1)([CH3:14])[C:10]([F:11])([F:12])[F:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: COc1nc(-c2nnc(C(C)(OCc3ccccc3)C(F)(F)F)o2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(-c2nnc(C(C)(OCc3ccccc3)C(F)(F)F)o2)c(N)cc1C(F)(F)F
Reaction time: 0.75 h

Procedure:
To a stirring solution of the tert-butyl 2-(5-(2-(benzyloxy)-1,1,1-trifluoropropan-2-yl)-1,3,4-oxadiazol-2-yl)-6-methoxy-5-(trifluoromethyl)pyridin-3-ylcarbamate (707 mg, 1.257 mmol) in DCM (10 ml) was added TFA (3 ml) and stirring continued for 45 min. The resulting mixture was washed with 2M NaOH and the organic phase separated using a phase separator. The solvent was removed in vacuo to afford the title product as a TFA salt; LC-MS Rt=1.42 min [M+H]+ 463.2 Method High pH_v003.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:26][C:27]#[N:28])[CH2:18][CH2:17][N:16]([C:19]([O:21]C(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.Cl.C(N(CC)CC)C.[O:37]1[C:41](C(Cl)=O)=[CH:40][CH:39]=[N:38]1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:26][C:27]#[N:28])[CH2:18][CH2:17][N:16]([C:19]([C:41]4[O:37][N:38]=[CH:39][CH:40]=4)=[O:21])[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccno1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCN(C(=O)c2ccno2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of tert-butyl 4-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (0.259 g, 0.643 mmol) in 2 mL of dioxane was added 4 M HCl in dioxane (4.0 mL). The reaction was stirred at room temperature for 30 min, then evaporated to dryness. To the resulting crude HCl salt in methylene chloride (5.0 mL) was added triethylamine (0.269 mL, 1.93 mmol) followed by isoxazole-5-carbonyl chloride (0.0744 mL, 0.771 mmol). The mixture was stirred at room temperature for 30 min, washed with saturated sodium bicarbonate, dried, and evaporated to dryness. The residue was used directly in next step (233 mg, 91%). LCMS (M+H) 398.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[Cl:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1B(O)O.BrC1C=CC(N)=CC=1Cl.FC(F)(F)C1C=CC(B(O)O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[Cl:10]
Reactant: Nc1ccc(I)c(Cl)c1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1ccc(-c2ccc(N)cc2Cl)c(Cl)c1

Procedure:
The title compound was prepared as described in Example 159 substituting 3-chloro-4-iodoaniline and (2-chloro-4-methoxyphenyl)boronic acid for 4-bromo-3-chloroaniline and (4-(trifluoromethyl)phenyl)boronic acid, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:35]([NH2:37])[CH3:36]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[NH:37][CH2:35][CH3:36]
Reactant: CCN
Reactant: Cc1ccc2ccccc2c1O
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: CCNc1c(C)ccc2ccccc12
Yield: 85 %

Procedure:
316 parts of 2-methyl-α-naphthol, 10 parts of triphenyl phosphite and 115 parts of ethylamine gas are heated for 20 hours at 230° C in a pressure autoclave. The further working up is carried out as described in Example 3. 315 parts of 2-methyl-N-ethyl-α-naphthylamine, boiling at 120° - 125° C/0.3 mm Hg (nD25 = 1.6145) are obtained, corresponding to a yield of 85% of theory.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.Cl>O1CCCC1.CCCCCC.O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(B(O)O)c(OC)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
576 μl of 1-bromo-2,4-dimethoxybenzene was dissolved in 5.8 ml of tetrahydrofuran and 3 ml of 1.6 mol/l solution of n-butyl lithium in hexane was added dropwise at −78° C. under argon atmosphere. Then, 1.1 ml of triisopropylborate was added, and after stirred at −78° C. for 40 minutes, the mixture was stirred at room temperature for 2 hours. To the reaction mixture, 40 ml of water and 1 ml of 5N-hydrochloric acid was added, and extracted with 50 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield 610.2 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:12]=[CH:15][N:16]([CH3:18])[CH3:17])#[N:10]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N

Procedure:
A 40.8 g portion of 5-nitro-anthranilonitrile and 40 ml of N, N-dimethylformamide dimethyl acetal were heated on a steam bath for 2 hours. The solvents were removed at reduced pressure and the residue was taken up in methylene chloride. After passing this solution through Magnesol the solvent was removed. After washing with ether 50.8 g of N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7](=[O:13])[CH2:8][NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=[CH:3]1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:9]1[CH2:8][C:7](=[O:13])[C:6]2[N:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:10]1(=[O:12])=[O:11]
Reactant: Cn1ccc2c1C(=O)CNS2(=O)=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ccc2c1C(=O)CN(CCCCl)S2(=O)=O
Yield: 45.2 %

Procedure:
A suspension of 200 mg (1 mmol) of Compound 13, 189 mg (1.2 mmol) of 1-bromo-3-chloropropane and 345 mg (2.5 mmol) of potassium carbonate in 5 ml of acetone was refluxed for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate/methylene chloride=1/30), whereby 125 mg of the title compound were obtained (yield: 45%).
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:33]/[OH:34])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48]>CN(C)C=O>[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:33]/[O:34][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COCCOCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCCOCCOC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
In 50 ml of dimethylformamide is dissolved 7.41 g of ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate hydrochloride and with stirring at room temperature, 4.15 g of potassium carbonate and 2.75 g of 1-bromo-2-(2-methoxyethoxy)ethane are added. The mixture is stirred for 48 hours, after which it is poured into 500 ml of ice water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (150 g) column and elution is carried out with hexane-ethyl acetate (1:1). The fractions rich in the desired compound are pooled and concentrated under reduced pressure to give 4.84 g of ethyl 2-(2-tritylaminothiazol4-yl)-(Z)-2-[2-(2-methoxyethoxy)ethoxyimino]acetate as a yellow foamy product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:9]2[C:10]([CH:15]=[CH2:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:9]2[C:10]([CH2:15][CH3:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: C=Cc1cc(O)cc2scc(CC(=O)OC)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(O)cc2scc(CC(=O)OC)c12
Reaction time: 8 h
Yield: 38.4 %

Procedure:
A mixture of methyl(6-hydroxy-4-vinyl-1-benzothiophen-3-yl)acetate (230 mg), 10% Pd—C (50% wet, 99 mg) and EtOAc (5 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (89 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@@H:17]1[CH:19]=[CH2:20])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:24]([O:23][C:21]([C@:16]1([NH:15][C:14]([C@@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)=[O:26])[CH2:18][C@@H:17]1[CH:19]=[CH2:20])=[O:22])[CH3:25]
Reactant: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC

Procedure:
Compound 13 was kept in 30% trifluoroacetic acid in dichloromethane and 1% MeOH for 2 hrs before it was concentrated to dryness. The residue was re-dissolved in dichloromethane and during stirring 1N NaOH was added to pH 10-11. The organic layer was separated and concentrated which gave 1.6 g of the title product. HPLC purity ca. 90% M+H+ 269.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][C@H:10]([CH3:12])[NH:9][C@H:8]([CH3:13])[CH2:7]1)=[O:5])[CH3:2].[C:14]1(C)[CH:19]=CC(S(OCCC)(=O)=O)=C[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][C@@H:8]([CH3:13])[N:9]([CH2:15][CH2:14][CH3:19])[C@@H:10]([CH3:12])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)N1C[C@@H](C)N[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CCO
Product: CCCN1[C@H](C)CN(C(=O)OCC)C[C@@H]1C
Reaction time: 5 h

Procedure:
A mixture of 25.8 grams of 1-ethoxycarbonyl-cis-3,5-dimethylpiperazine, 38.6 grams of propyl 4-toluene-sulfonate, 90 ml. of absolute ethanol and 9.5 grams of sodium carbonate is stirred and heated to reflux. After 30 minutes of reflux, vigorous evolution of carbon dioxide begins and continues for about 5 hours. Refluxing is continued for a total of 22 hours. The reaction mixture is then cooled and filtered and the solvent is evaporated. The resulting residue is mixed with 300 ml. of aqueous 1 N sodium hydroxide solution and the mixture is extracted with ethyl ether. The ether extract is washed successively with 100 ml. of aqueous 1 N sodium hydroxide and 100 ml. of water and then dried over anhydrous sodium sulfate. The organic solution is then treated with charcoal and the solvent is evaporated to leave a residue which is purified by chromatography to give 4-ethoxycarbonyl-cis-2,6-dimethyl-1-propylpiperazine. If 1-ethoxycarbonyl-cis-2,6-dimethylpiperazine is reacted with propyl 4-toluenesulfonate according to this same procedure, the product obtained is 1-ethoxycarbonyl-cis-2,6-dimethyl-4-propylpiperazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15](=[O:17])[NH2:16])=[N:13][CH:12]=[C:11]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1.FC(F)(F)C(O)=O>ClCCCl>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]([NH2:16])=[O:17])=[N:13][CH:12]=[C:11]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ncc(Oc2cccc([N+](=O)[O-])c2)nc1Nc1ccc(N2CCNCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a mixture of tert-butyl 4-(2-bromo-4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (682 mg) and 1,2-dichloroethane (7 mL) was added trifluoroacetic acid (3 mL) under ice-cooling, and followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then diluted with chloroform, and neutralized with a 10% aqueous potassium carbonate solution. After extracting with chloroform, the organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3-{[3-bromo-4-(piperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (523 mg) as a yellow amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][C:19]#[N:20])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[O-].[Na+].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12](/[C:18](/[C:19]#[N:20])=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CC#N)cc2C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(/C(C#N)=C/c3ccccc3)cc2C1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To a solution of 0.231 mmol tert-butyl-7-(cyanomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in 2 ml ethanol were added 0.278 mmol of NaOEt solution (21%) and 0.254 mmol benzaldehyde. The mixture was stirred at room temperature over night. The mixture was diluted with ethanol and H2O, and a white precipitation observed. The solid was filtered off and washed with ethanol and H2O. The white solid was dissolved in methanol. Evaporation of the solvent gave 64 mg (77%) of solid material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:33])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-methyl-3-(3-trifluoromethyl-phenyl)-propyl]-amine (Enantiomer A) and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[CH3:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: CSc1nccc(Cl)n1
Reactant: Cc1cc(B(O)O)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: CSc1nccc(-c2ccnc(C)c2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-pyrimidine (781 mg, 4.86 mmol) in degassed nPrOH (55 ml), 2-methylpyridine-4-boronic acid (800 mg, 5.84 mmol), Na2CO3 (619 mg, 5.47 mmol), triphenylphosphine (127 mg, 0.486 mmol) and Pd(OAc)2 (32 mg, 0.15 mmol) were added. The mixture was stirred at 100° C. for 1 hour. The solvent was evaporated under vacuum, and the crude was dissolved in DCM and washed with water. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (20-0.1-0.2) to give 990 mg of the title compound (93% yield).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[C:10]1=[O:25])=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C1(OC)C=CC=CC=1>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:8][C@H:9]1[CH:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[C:10]1=[O:25]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OC1CCCCC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1[C@H](N)C(=O)N1OCC(=O)OC1CCCCC1

Procedure:
(3S-trans)-[[3-[(t-Butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid. cyclohexyl ester (2.23 g) prepared analogously to the procedure of example 91A was dissolved in a solution of 25 ml of trifluoroacetic acid and 2.5 ml of anisole at -10° C. The mixture was evaporated in vacuo 25 minutes later and the residue was stirred with ether, filtered off and dried over P2O5 to give colorless crystals of (3S)-[[3-amino-4 methyl2-oxo-1-azetidinyl]oxy]acetic acid, cyclohexyl ester, trifluoroacetate salt (yield 1.53). The salt (1.50 g) was suspended in 30 ml of acetonitrile. MSTFA (2.37 ml) was added at 0° C. and the solution was allowed to stand overnight. After evaporating in vacuo, the residue (1.75 g) was dissolved in dry tetrahydrofuran (25 ml), 1.4 g of (Z)-2-amino-α-methoxyimino)-4-thiazoleacetic acid, 1-hydroxybenzotriazole ester was added and the mixture was stirred at room temperature for 4 hours. Tetrahydrofuran was removed in vacuo at 30° C., the residue was taken up in ether, shaken with ice-cold aqueous NaHCO3 (in) and twice with cold water. The dried ethyl acetate layer was evaporated in vacuo. The resulting oil (2.14 g) chromatographed on silica gel with ethyl acetate to give 1.58 g of the title compound; melting point 85°-90° C. dec.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C-]#N.[K+]>C(O)C.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([C:7]([CH:7]([C:6]3[CH:1]=[CH:2][C:3]4[O:11][CH2:10][O:9][C:4]=4[CH:5]=3)[OH:8])=[O:8])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc2c(c1)OCO2)C(O)c1ccc2c(c1)OCO2

Procedure:
A solution of piperonal (5 g) in ethanol (6.5 ml) was treated with a solution of potassium cyanide (0.5 g) in water (5 ml), then refluxed for 5 h. The resultant precipitate was filtered off, washed with water then crystallized from ethanol to give DC-0001B (124 g, 45%) as an off white crystalline solid.