Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.O[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]2[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([O:43][CH3:44])=[O:42])[CH2:34]1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[CH3:44][O:43][C:41]([C:40]1[CH:45]=[CH:46][CH:47]=[CH:48][C:39]=1[N:35]1[CH2:36][CH2:37][CH2:38][CH:33]([CH2:32][N:24]2[C:20](=[O:30])[C:21]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:22]3[C:23]2=[O:25])[CH2:34]1)=[O:42]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)c1ccccc1N1CCCC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccccc1N1CCCC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
Triphenylphosphine (1.68 g, 6.20 mmol) and phthalimide (799 mg, 5.43 mmol) were added to methyl 2-[3-(hydroxymethyl)piperidin-1-yl]benzoate (1.29 g, 5.17 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 10 min and a 40% diethyl azodicarboxylate/toluene solution (3.52 mL, 7.76 mmol) was added. The mixture was then stirred at room temperature for 8 hours. Subsequently, water was added and the mixture was extracted with ethylacetate. The extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 1.85 g (95%) of the desired compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Fc1ccc(CBr)cc1Cl
Product: NC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 43 %

Procedure:
The titled compound was prepared in 43% yield from (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (75 mg, 0.237 mmol) and 4-bromomethyl-2-chloro-1-fluoro-benzene (56 mg, 0.249 mmol) according to the procedure described for Example 3: 1H NMR (500 Mz, DMSO) δ 7.80 (d, 2 H, J=8.5), 7.63 (d, 2 H, J=8.8), 7.38–7.27 (m, 4 H), 6.67 (br s, 1 H), 4.52 (ABq, 2 H, Δv=92.1, Jab=17.1), 3.87, 2.79 (m, 1 H), 2.44 (m, 1 H), 1.78 (m, 1 H), 1.64 (m, 2 H), 1.42–1.20 (m, 3 H), 0.90 (m, 1 H); MS m/e 481.2 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:9][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: NCCOc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of 2-(4-bromophenoxy)ethanamine (500 mg, 2.3 mmol) in CH2Cl2 (20 mL) was added triethylamine (700 mg, 6.9 mmol) and acetic anhydride (470 mg, 4.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give a yellow residue. The crude product was diluted with ethyl acetate (20 mL), washed with 1 N HCl followed by saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to give N-[2-(4-bromophenoxy)ethyl]acetamide (400 mg, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 2 H), 6.76 (d, 2 H), δ 5.89 (m, 1 H), 4.00 (m, 2 H), 3.67 (m, 2 H), δ 2.01 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[S:15](=[O:18])(=[O:17])[NH2:16])=[O:6].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:10][C:9]=1[S:15](=[O:18])(=[O:17])[NH2:16])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC(=O)Nc1ccc(N)cc1S(N)(=O)=O
Solvent: c1ccncc1
Product: COC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O

Procedure:
mesylating the N-(4-amino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (IV), via addition of methanesulfonyl chloride to a suspension of N-(4-amino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (IV) and pyridine to form the intermediate compound N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (V).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH:9]([CH3:10])[CH2:8][N:7](C(OCC)=O)[CH2:6][CH:5]1[CH3:16])[CH3:2]>[OH-].[Na+]>[CH2:1]([NH:3][CH:4]1[CH:5]([CH3:16])[CH2:6][NH:7][CH2:8][CH:9]1[CH3:10])[CH3:2]
Reactant: CCNC1C(C)CN(C(=O)OCC)CC1C
Agent: [Na+]
Agent: [OH-]
Product: CCNC1C(C)CNCC1C

Procedure:
The Mixture B of isomers of 4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine (2.1 g, 0.92 mmol) was stirred in 5 N NaOH solution (20 ml) at 100° C. for 96 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to afford Mixture B of isomers 4-ethylamino-3,5-dimethylpiperidine as oil. Yield 1.34 g (93.2%), C9H20N2, m/z 157 (M+1), PMR (CDCl3): 0.94 (dd, 6H), 1.12 (t, 3H), 1.5-1.8 (m, 3H, D2O exchangeable), 1.9 (m, 1H), 2.28 (m, 2H), 2.46 (m, 1H), 2.62-3.0 (m, 4H).
Reaction SMILES: [C:1]1([N:14]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]2=[O:20])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:2]=1.[CH3:21][C:22](C)=[O:23]>>[C:18]1(=[O:19])[O:20][C:15](=[O:23])[CH:16]=[CH:17]1.[CH:22]([O:23][CH3:1])=[CH2:21].[C:1]1([N:14]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]2=[O:20])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:2]=1
Reactant: CC(C)=O
Agent: O=C1C=CC(=O)N1c1cccc(N2C(=O)C=CC2=O)c1
Product: C=COC
Product: O=C1C=CC(=O)O1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A 2-liter stainless steel high pressure reactor was charged with 513.88 g of acetone and 0.201 g of N,N′-1,3-phenylenedimaleimide. The reactor was sealed and purged three times with nitrogen gas ending with a head pressure of 25 psi N2. Then the temperature was raised to 70° C. during a 40 min period. When the temperature reached 60° C., 111.88 ml of molten maleic anhydride was introduced. At 80° C., separate feeds of 175.35 ml of methyl vinyl ether and 1.17 g of decanoyl peroxide in 33 g of acetone were introduced into the reactor over a period of 3 hours, with the methyl vinyl ether feed begun 10 min. before the decanoyl peroxide-acetone solution. After the feed was completed, the reactor was maintained at 80° C. for an additional half-hour. The reactor was then cooled to provide a thick, viscous light amber colored solution of the desired copolymer product in acetone.
Reaction SMILES: [C:1]1([N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18]N(C)C=O.[H-].[Na+].P(OC)(OC)(OC)=O>O>[C:1]1([N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]([CH3:18])[C:8]2=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCc2cccnc2N1c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: COP(=O)(OC)OC
Solvent: O
Product: CN1Cc2cccnc2N(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2.2 g of 1-phenyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 20 ml of dimethylformamide was added 0.5 g of approximately 50% sodium hydride, and the mixture was allowed to stand at room temperature for 30 minutes. To this was further added dropwise 4.2 g of trimethyl phosphate and the resulting mixture was heated at a temperature of 170° - 180° C in a sealed-tube for 7 hours. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was diluted with water, extracted with ether and dehydrated. The ether was removed by evaporation to leave a residue. This residue was recrystallized from a mixture of ether and petroleum ether to yield 1.7 g of 1-phenyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 172° - 173° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[O:14][CH2:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(CCO)C(O)=C1OCc1ccccc1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1

Procedure:
reacting a 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone of the formula, ##STR14## wherein Bn is as hereinbefore defined with one equivalent of BnBr and one equivalent of triethlyamine in THF for 5 hours at 65--C to provide 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone of the formula, ##STR15## wherein Bn is as hereinbefore defined;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:18][C:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CS(C)=O>[CH3:18][C:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)C1(C)CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(C)CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 60 °C
Yield: 94.2 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (2.0 g, 12.62 mmol) in DMSO (20 mL) was added sodium carbonate (6.70 g, 63.08 mmol) followed by methyl 4-methylpiperidine-4-carboxylate hydrochloride (2.44 g, 12.62 mmol). The reaction mixture was heated to 60° C. for 2 hours. The reaction mixture was poured onto water (100 mL) and the suspension filtered, washed with water (4×150 mL) and dried to leave the title compound as a yellow solid (3.32 g, 11.89 mmol, 94%); 1H NMR (CDCl3) δ 1.26 (s, 3H), 1.46-1.52 (m, 2H), 2.21-2.25 (m, 2H), 3.26-3.32 (m, 2H), 3.74 (s, 3H), 4.16-4.20 (m, 2H), 6.56 (d, 1H), 8.18 (d, 1H), 9.03 (s, 1H); MS m/e MH+ 280.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13]C[N:11]([S:15]([C:18]2[C:19]3[C:20]([Br:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33]C(N[C@H]1CCN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:11]([S:15]([C:18]2[C:19]3[C:20]([Br:28])=[CH:21][N:22]=[C:23]([O:33][CH3:29])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Product: COc1ncc(Br)c2c(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)cccc12

Procedure:
3-(tert-Butoxycarbonylamino)-1-(2-oxy-4-bromo-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 3) can be obtained by using Intermediate 1 in the method of Example 6-1, Step A instead of Intermediate 1a, and then used in the method of Step B to obtain 3-(tert-butoxycarbonylamino)-1-(4-bromo-1-methoxy-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 4), and then Intermediate 4 can be used in the method of Step C to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][C@H:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:32][OH:33].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>C(Cl)Cl>[OH:33][CH2:32][C@H:31]([NH:30][C:27]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[C@H:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]1)=[O:29])[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)C[C@@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@H](CO)NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d, (R)-2-amino-4-methyl-pentan-1-ol (35.16 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethyl-3-methyl-butyl)-amide (26.2 mg, 24.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([Cl:23])=[O:19])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(/C=C/C=C/C(=O)O)cc(OC)c1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(/C=C/C=C/C(=O)Cl)cc(OC)c1OC

Procedure:
A solution of 286 mg (1.1 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid in anhydrous dimethylformamide-methylene chloride (0.1 ml-10 ml) was cooled in an ice bath. To the solution was added 0.12 ml (1.3 mmol) of oxalyl chloride with stirring. The ice bath was removed, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl chloride.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[C:33]([O-:36])([OH:35])=O.[Na+].CN(C=O)C>O>[C:21]([OH:20])(=[O:17])/[CH:22]=[CH:23]/[C:33]([OH:36])=[O:35].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH:4]2[C:9]3=[N:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:8]3[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]2)[CH2:29][CH2:28]1
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCC2CN(C)C(=O)n3c2nc2ccccc23)CC1
Product: O=C(O)/C=C/C(=O)O
Yield: 92.1 %

Procedure:
A mixture of 4.0 g (0.015 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazole-1(2H)-one, 2.93 g (0.015 mol) of 1-(2-methoxyphenyl)piperazine, 9 g of NaHCO3, 0.5 g of Kl, and 30 mL of DMF was heated on a steam cone for 18 h. The reaction mixture was poured into 400 mL of H2O and extracted with 2×100 mL CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated by rotary evaporation. The resulting oil was purified by preparative HPLC eluting with acetone and using silica gel as the stationary phase. Like fractions were combined and concentrated by rotary evaporation to an oil. The oil was treated with fumaric acid in 2-propanol to give 3.7 g (42%) of the salt, mp 100°-108° C. dec.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.N[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32](C=O)C>CO>[C:31]([C:23]1[CH:22]=[CH:21][C:20]([O:24][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:19][CH:18]=1)#[N:32]
Reactant: CN(C)C=O
Reactant: Nc1cccc(O)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
1-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (30 mg, 0.13 mmol), 3-aminophenol (43 mg, 0.39 mmol), and potassium carbonate (90 mg, 0.65 mmol) were suspended in DMF (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, and filtered through a membrane. The crude product was purified via prep-LC-MS to provide 132 (3 mg, 8% yield) as a solid. LC-MS (M+H=304, obsd.=304). 1H NMR (400 MHz, d6-DMSO): δ 12.09 (s, 1H), 9.04 (d, 1H), 8.42 (dd, 1H), 8.28 (d, 1H), 7.78 (dt, 1H), 7.69 (t, 1H), 7.13 (t, 1H), 6.63 (d, 1H), 6.52 (dd, 1H), 6.39 (m, 2H), 5.54 (s, 2H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([OH:12])=[O:11].[CH3:17][S:18]SC>O1CCCC1.CCOCC>[F:6][C:7]1[C:8]([S:18][CH3:17])=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([OH:12])=[O:11]
Reactant: CSSC
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSc1c(C(=O)O)ccc(F)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
n-Butyllithium (2.5m in hexane, 35 ml) was added with cooling to a solution of 3,4-difluorobenzoic acid (5.5 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred for 2 hours at -70° C. A solution of dimethyl disulphide (19.8 g) in tetrahydrofuran was added and the mixture was stirred at -70° C. for 1.5 hours. It was allowed to warm to room temperature, diluted with ether and washed with water. The aqueous layer was acidified to pH 1 and extracted with ether, washed with water, dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was recrystallised from a mixture of cyclohexane and ether to give 3,4-difluoro-2-(methylsulphenyl)benzoic acid (5.9 g) as a white solid, m.p. 149.2°-149.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of 3-bromoaniline (3.21 g, 18.60 mmol) in dry tetrahydrofuran (45 mL) were added triethylamine (2.82 g, 27.91 mmol) and phenylacetyl chloride 93.45 g, 22.30 mmol) at 0° C. The reaction warmed to room temperature and stirred for 4 h. The reaction mixture was treated with 2.0 N aqueous hydrochloric acid (20 mL) at 0° C. and diluted with ethyl acetate (300 mL). The organic layer was washed with water (20 mL), saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford crude N-(3-bromophenyl)-2-phenylacetamide (4.84 g, 86% yield) which was used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]2=[N:4][CH:3]=1.CS[C:17]1[N:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[CH:20]=[CH:19][N:18]=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:37]1([NH:36][C:17]2[N:18]=[C:19]([C:2]3[N:6]4[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]4=[N:4][CH:3]=3)[CH:20]=[CH:21][N:22]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OCCNc1nccn2c(Br)cnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: Nc1ccccc1
Product: OCCNc1nccn2c(-c3ccnc(Nc4ccccc4)n3)cnc12

Procedure:
2-[3-(2-Phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol was prepared by a process analogous to that described in Example 12 starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (from Example 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and aniline. LC-MS: [M+H]+ 348.3.
Reaction SMILES: NC1C(O)=CC(Br)=CN=1.N.Br[C:12]1[N:17]=[C:16]2[O:18][CH:19]=[N:20][C:15]2=[CH:14][CH:13]=1.BrC1C=C2OC=NC2=NC=1.[CH3:31][N:32](C(OC(C)(C)C)=O)[CH:33]([CH2:35][CH:36]=[CH2:37])[CH3:34]>>[CH3:31][NH:32][CH:33]([CH2:35]/[CH:36]=[CH:37]/[C:12]1[N:17]=[C:16]2[O:18][CH:19]=[N:20][C:15]2=[CH:14][CH:13]=1)[CH3:34]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Brc1ccc2ncoc2n1
Agent: Brc1cnc2ncoc2c1
Agent: N
Agent: Nc1ncc(Br)cc1O
Product: CNC(C)C/C=C/c1ccc2ncoc2n1

Procedure:
In another example, 6-bromooxazolo[4,5-b]pyridine, when submitted sequentially to palladium catalyzed coupling to N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine and deprotection with trifluoroacetic acid, gives (4E)-N-methyl-5-(6-oxazolo[4,5-b]pyridinyl)-4-penten-2-amine. The requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5-bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M-C. Viaud et al., Heterocycles 41: 2799-2809 (1995). The use of other carboxylic acids produces 2-substituted-6-bromooxazolo[4,5-b]pyridines, which are also substrates for the Heck reaction. The synthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine (Aldrich Chemical Company). Thus, 5-bromo-3-pyridinol (produced from furfurylamine according to U.S. Pat. No. 4,192,946) can be chlorinated, using methods described by V. Koch et al., Synthesis, 499 (1990), to give 2-chloro-5-bromo-3-pyridinol, which in turn can be converted to 2-amino-5-bromo-3-pyridinol by treatment with ammonia. 5-Bromooxazolo[5,4-b]pyridine, isomeric by orientation of ring fusion to the previously described 6-bromooxazolo[4,5-b]pyridine, can also be used in the Heck coupling with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. Subsequent removal of the tert-butoxycarbonyl protecting group provides (4E)-N-methyl-5-(5-oxazolo[5,4-b]pyridinyl)-4-penten-2-amine. The 5-bromooxazolo[5,4-b]pyridine can be synthesized from 3-amino-5-bromo-2-pyridinol (3-amino-5-bromo-2-pyridone) by condensation with formic acid (or a derivative thereof) as described above. 3-Amino-5-bromo-2-pyridinol can be made by bromination (using techniques described by T. Batkowski, Rocz. Chem. 41: 729-741 (1967)) and subsequent tin(II) chloride reduction (according to the method described by S. X. Cai et al., J. Med. Chem. 40(22): 3679-3686 (1997)) of commercially available 3-nitro-2-pyridinol (Aldrich Chemical Company).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[C:12]([CH:22]=[CH:21][CH:20]=1)[O:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)=[O:16])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 88.2 %

Procedure:
A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp. overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic phases were sequentially washed with water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g). Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene