Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1>OS(O)(=O)=O.C(Cl)Cl>[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Nc1ccc(Br)c([N+](=O)[O-])c1
Temperature: 20 °C

Procedure:
Conc. nitric acid (15.8 mL, 376.9 mmol) was added to a solution of 4-bromoaniline (40 g, 232.5 mmol) in H2SO4/CH2Cl2 (400 mL, 1:1, v/v) dropwise at 0° C. under an atmosphere of N2. The cooling bath was removed and the mixture was stirred at 20° C. until the starting material was consumed (about 1 h). The reaction mixture was poured onto water and neutralized with NaOH solution to pH=9 and extracted with DCM. The organic layer was dried, filtered and evaporated in vacuo to afford the crude product 4-bromo-3-nitro-aniline, which was used directly in the next step.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[CH:5]([N:9]=[N:10][C:11]([N:17]=[C:18]=[O:19])([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH2:7][CH3:8])[CH3:6]>O>[CH:5]([N:9]=[N:10][C:11]([NH:17][C:18]([O:2][CH3:1])=[O:19])([CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:12])([CH2:7][CH3:8])[CH3:6]
Reactant: CO
Reactant: CCC(C)N=NC(C)(CC(C)C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(C)N=NC(C)(CC(C)C)NC(=O)OC
Temperature: 25 °C

Procedure:
To 25 ml of stirred methanol in a 125 ml erlenmeyer flask was slowly added 1.2 grams (0.028 moles) of 57% sodium hydride. The solution was cooled to 25° C. in a cold water bath and 5.9 grams (0.028 moles) of 2-sec.-butylazo-2-isocyanato-4-methylpentane (from Example XVII) was added dropwise over 5 minutes. The reaction was stirred an additional hour at room temperature, poured into 200 ml water, the product extracted with 100 ml pentane, washed with 100 ml saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 3.9 grams (57.3% crude yield). The infrared spectrum was in agreement with the structure of 2-sec-butylazo-2-(methoxycarbonylamino)-4-methylpentane (strong carbonyl band at 1740 cm-1, sharp NH at 3375 cm-1 and no isocyanate band at 2125-2225 cm-1).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](O)=[O:18])[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1)[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:1])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:34]([CH2:32][CH3:33])[C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[O:18])[N:6]=1)=[O:4]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CCNc1nccs1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21)c1nccs1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Weigh 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid, 23.0 mg HOBt, and 38.3 mg EDC into a 13×100 mm screw cap tube. Add 19.2 mg N-ethyl-1,3-thiazol-2-amine followed by 1 mL DMF and 45.2 mg DIEA in that order. The mixture was stirred at 45° C. for two hours and purified by RP-HPLC using 50-90% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as a white solid. LC-MS: 3.96 min. (m/Z=423.2, 245.1, 273.1, 401.2).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:25](ON1C(=O)CCC1=O)=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[O:19]C(C)(C)C)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:42][C@H:43]([C:48]([OH:50])=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45].[CH3:51][N:52]1[C@@H:69]2[CH2:70][C:57]3[CH:58]=[CH:59][C:60]([O:71][CH3:72])=[C:61]4[O:62][C@H:63]5[C:64]([CH2:66][CH2:67][C@@H:68]2[C@:55]5([C:56]=34)[CH2:54][CH2:53]1)=[O:65]>>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:25]([NH:42][C@H:43]([C:48]([OH:50])=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45])=[O:26])[CH2:16][CH2:17][C:18](=[O:19])[OH:24])=[O:13])[CH2:3][CH2:4][C:5](=[O:6])[OH:11].[CH3:51][N:52]1[C@@H:69]2[CH2:70][C:57]3[CH:58]=[CH:59][C:60]([O:71][CH3:72])=[C:61]4[O:62][C@H:63]5[C:64]([CH2:66][CH2:67][C@@H:68]2[C@:55]5([C:56]=34)[CH2:54][CH2:53]1)=[O:65]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H](N)CCC(=O)O)C(=O)O

Procedure:
Glu-Glu-Ile-Hydrocodone was prepared by similar methods except the amino acid starting material was Boc-Glu(OtBu)-Glu(OtBu)-OSu and the conjugate starting material was Ile-Hydrocodone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.I[CH:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (50.0 g, 318 mmol, 1 equiv), 2-iodopropane (96.0 mL, 955 mmol, 3 equiv), and K2CO3 (132.0 g, 955 mmol, 3 equiv) in acetone (1 L) was heated to reflux for ON. After cooling to RT, the solid was filtered-off and rinsed with DCM, then the filtrate was concentrated to dryness. The residue was taken in water, EtOAc, and 1N NaOH. The layers were separated, and the organic layer was washed with 1N NaOH 1×. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 4-fluoro-2-isopropoxy-1-nitrobenzene (49.3 g, 78%) as a yellow-brown liquid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 7.91-7.96 (dd, 1H, J=6.3 Hz, 9.0 Hz), 7.31-7.35 (dd, 1H, J=2.4 Hz, 11 Hz), 6.88-6.95 (m, 1H), 4.77-4.89 (hep, 1H, J=6.0 Hz), 1.27-1.29 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −102.4 (sextet); m/z=200 (M+H)+.
Reaction SMILES: Br[C@@H:2]([CH2:8][N:9]([CH2:19][C@@H:20](Br)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:27]([N:34]1[C@H:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][N:9]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:19][C@@H:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)[C@H](Br)CN(C[C@H](Br)C(=O)OCC)S(=O)(=O)c1ccccc1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CN(S(=O)(=O)c2ccccc2)C[C@@H](C(=O)OCC)N1Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 112b (20g, 38.8 mmol) in toluene (100 ml) was added BnNH2 (12.48 g, 116.5 mmol). The reaction mixture was stirred at 90° C. for 3 h. Then the mixture was purified through a silica gel column eluting with PE:EA=50:1 to 10:1 to give 112c as a white crystal (10.7 g, 60%) MS: [M+H]+: 461
Reaction SMILES: [ClH:1].F[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1.[Cl-].[Cl:22]C1C=CC=CC=1C[Zn+]>>[ClH:22].[Cl:1][C:17]1[CH:18]=[CH:19][CH:20]=[CH:3][C:4]=1[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1
Reactant: Clc1ccccc1C[Zn+]
Reactant: CC1(C)CNc2cc(Cc3ccccc3F)ncc21
Agent: Cl
Agent: [Cl-]
Product: CC1(C)CNc2cc(Cc3ccccc3Cl)ncc21

Procedure:
Prepared in an analogous manner to 6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (Preparation 119) using 2-chlorobenzylzinc chloride instead of 2-fluorobenzylzinc chloride. MS: [M+H]+=273.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27]
Reactant: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred brown solution of 4-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester (95.97 g, 233.8 mmol) in methylene chloride (800 mL), was added trifluoroacetic acid (33.87 mL, 455.9 mmol), and the mixture was stirred at room temperature overnight. Sat. sodium bicarbonate (500 mL) was added to the solution, and the mixture was stirred for 10 minutes. The organic layer was separated, dried over magnesium sulfate, and evaporated to give 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown oil (64.36 g, 88% crude yield). The product was used in the next step without further purification.
Reaction SMILES: C(OC([NH:8][CH:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[N:26]=[C:25]4[C:20]([C:21](=[O:40])[C:22]([C:35]([O:37]CC)=[O:36])=[CH:23][N:24]4[C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[CH:19][C:18]=3[F:41])[CH2:13][CH2:12]2)[CH2:10]1)=O)(C)(C)C.[ClH:42]>C(OCC)(=O)C>[ClH:42].[NH2:8][CH:9]1[C:11]2([CH2:12][CH2:13][N:14]([C:17]3[N:26]=[C:25]4[C:20]([C:21](=[O:40])[C:22]([C:35]([OH:37])=[O:36])=[CH:23][N:24]4[C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[CH:19][C:18]=3[F:41])[CH2:15][CH2:16]2)[CH2:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC4(CC3)CC4NC(=O)OC(C)(C)C)c(F)cc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CC12CCN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3-c1ccc(F)cc1F)CC2
Yield: 38 %

Procedure:
A solution of the compound of step A (441 mg, 0.77 mmol) in ethyl acetate (9 ml) and 3N hydrogen chloride (9 ml) was heated to reflux overnight. solvents were removed in vacuo and the residue was recrystallized from methanolacetonitrile to give the title product as a yellow solid, mp 217° C. (decomap.), (133 mg, 0.29 mmol, 38% yield).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[O:35]=[C:36]([CH3:40])[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:37](=[O:38])[C:36](=[O:35])[CH3:40])[CH2:31][CH2:30]1)=[O:28]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Reactant: CC(=O)C(=O)O
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: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 13.5 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (157.5 mg, 0.34 mmol), 2-oxopropanoic acid (0.15 ml (d=1.26), 2.15 mmol), DIPEA (0.5 ml, 3 mmol), and HATU (258.6 mg, 0.68 mmol) were mixed in DMF (20 ml), the resulting reaction mixture was stirred at room temperature for 60 h until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (50 ml each, the water phase was extracted with DCM (50 ml). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether: Ethyl Acetate=1:2) to afford the desired product (20 mg, 13.5%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-])=O)([CH3:6])[C:3]([OH:5])=[O:4].[H][H]>O1CCCC1.[Ni]>[CH3:6][C:2]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[NH2:15])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(Nc1cc(Cl)ccc1[N+](=O)[O-])C(=O)O
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(Nc1cc(Cl)ccc1N)C(=O)O

Procedure:
Using a one-liter autoclave, 53.4 g (0.206 mol) of 2-methyl-(5'-chloro-2'-nitroanilino)-propionic acid in solution in 500 ml of tetrahydrofuran are hydrogenated in the presence of 17 g of Raney nickel. Hydrogen pressure in the cold: 120 kg. Temperature 60° C. Duration: 1 hour. Pressure drop:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([C:31]1[C:39]2[N:38]=[C:37]([CH2:40][NH:41]C(OC(C)(C)C)=O)[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1)=[O:30])[C:6]([N:8]([CH3:24])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7]>FC(F)(F)C(O)=O>[NH2:41][CH2:40][C:37]1[NH:36][C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:29]([NH:28][C:27]3[CH:26]=[CH:25][C:5]([C:6]([N:8]([CH3:24])[C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=4[O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:30])[C:39]=2[N:38]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCc2ccccc2)ccc1NC(=O)c1cccc2[nH]c(CNC(=O)OC(C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCc2ccccc2)ccc1NC(=O)c1cccc2[nH]c(CN)nc12
Yield: 59.1 %

Procedure:
A solution of 3-methoxy-N-methyl-N-(4-methyl-2-benzyloxyphenyl)-4-[2-(tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (260 mg) in 90% trifluoroacetic acid (2 ml) was stirred at ambient temperature for 2 hours and the solvent was evaporated in vacuo. The residue was stirred with chloroform (10 ml) and saturated aqueous sodium hydrogencarbonate (10 ml) and the organic phase was separated. The solution was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by NH type silica gel column (chloroform) to give 4-(2-aminomethyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-(4-methyl-2-benzyloxyphenyl)benzamide (130 mg).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH2:20])[CH2:9]1)=O)(C)(C)C.[BrH:21]>>[BrH:21].[BrH:21].[OH:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]=[CH:9][C:10]([NH2:20])=[CH:11]2
Reactant: COc1ccc2c(c1)C=C(N)CN2C(=O)OC(C)(C)C
Agent: Br
Product: Nc1cnc2ccc(O)cc2c1
Temperature: 0 °C

Procedure:
A stirred suspension of N-tert-butyloxycarbonyl-6-methoxy-3-aminoquinoline (Example 134, Step F) (0.274 g, 1 mmol) in HBr (48%, 2.5 mL) was heated at reflux for 48 h. The reaction was cooled to 0° C., and the yellow crystalline solid was filtered off and washed with a small amount of ice-cold water followed by acetone. The yellow crystalline solid was dried over P2O5 to give 6-hydroxy-3-aminoquinoline di-hydrobromide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O.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>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2F)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
To a stirred solution of dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate T4.1 (1.60 g, 4.7 mmol) in DMF (9.4 mL, 4.7 mmol) at 23° C. was added 2-fluorophenylboronic acid (0.98 g, 7.0 mmol, commercially available from Sigma-Aldrich, St. Louis, Mo., USA), potassium carbonate (1.9 g, 14 mmol), and then tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol). The reaction mixture was heated to 90° C. and the reaction was stirred for 22 hours. The reaction was then cooled to room temperature, diluted with water, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield T28.1 as a colorless oil (1.10 g, 82% yield).
Reaction SMILES: [ClH:1].Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:48](=O)([O:57]C1C=CC([N+]([O-])=O)=CC=1)[O:49][CH:50]([O:53][C:54](=[O:56])[CH3:55])[CH2:51][CH3:52]>CN(C)C=O>[ClH:1].[C:54]([O:53][CH:50]([O:49][C:48]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:57])[CH2:51][CH3:52])(=[O:56])[CH3:55]
Reactant: CCC(OC(C)=O)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2=O)cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCN(C(=O)OC(CC)OC(C)=O)CC3)CC2=O)cc1

Procedure:
The title compound was prepared in a yield of 115 mg (100%) as a free base from 101 mg of ethyl 4-[[2-oxo-4-(piperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in the same manner as in Example 8 except that N,N-dimethylformamide, proton sponge and 1-acetoxypropyl 4-nitrophenyl carbonate were used in an amount of 2 ml, 101 mg and 82.8 mg, respectively.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].C([Li])CCC.[C:13](OCC)(=[O:15])[CH3:14]>C(OCC)C>[C:13]([C:4]1[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=1)(=[O:15])[CH3:14]
Reactant: CCOC(C)=O
Reactant: Cc1ncsc1C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1nc(C)c(C)s1
Temperature: -70 °C
Reaction time: 0.83 h
Yield: 66 %

Procedure:
A solution of 4,5-dimethylthiazole (2.0 g, 17.67 mmol, 1 eq.) in dry diethyl ether (20 mL) was added slowly dropwise, over approximately 30 minutes, to a solution of butyllithium (7.8 mL, 19.44 mmol, 2.5M, 1.1 eq.) in dry diethyl ether (20 mL) at −70° C. The resultant solution was stirred at −70° C. for 30 minutes, −30° C. for 20 minutes and then re-cooled to −70° C. Dry ethyl acetate (3.11 g, 3.5 mL, 35.34 mmol, 2 eq.) was added in one portion to the deep red solution and the cooling bath was removed. After 50 minutes stirring at room temperature the reaction mixture was poured into saturated NaHSO4 and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated Na2CO3 (1×50 mL), brine (1×50 mL), dried over solid Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the resultant greenish, mobile oil was purified by column chromatography (15% ethyl acetate in hexanes) on silica gel giving a yellow oil (1.81 g, 66% yield): 1H (400 Mhz, CDCl3) δ 2.4(3H, s), 2.5(3H, s), 2.7(3H, s).
Reaction SMILES: CC1(C)CN2C(=[O:17])C=C(C3C=CN=CC=3)N=C2NC1.[H-].[Na+].N1[C:30]2[CH2:29][C@H:28]([CH2:31][N:32]3[C:37]4=[N:38][C:39]([C:43]5[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=5)=[CH:40][C:41](=[O:42])[N:36]4[CH2:35][C:34]([CH3:50])([CH3:49])[CH2:33]3)[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[O:17]1[C:30]2[CH:29]=[CH:23][CH:24]=[CH:25][C:26]=2[CH2:27][CH:28]1[CH2:31][N:32]1[C:37]2=[N:38][C:39]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)=[CH:40][C:41](=[O:42])[N:36]2[CH2:35][C:34]([CH3:49])([CH3:50])[CH2:33]1
Reactant: CC1(C)CNc2nc(-c3ccncc3)cc(=O)n2C1
Reactant: CC1(C)CN(C[C@@H]2Cc3cccnc3C2)c2nc(-c3ccncc3)cc(=O)n2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(CC2Cc3ccccc3O2)c2nc(-c3ccncc3)cc(=O)n2C1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 22 %

Procedure:
A suspension of 0.51 g (2 mmol) of 7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 10 ml of anhydrous dimethylformamide was treated with 96 mg (2 mmol) of sodium hydride (50% suspension in mineral oil) and the resulting mixture was stirred at 40° C. for 40 min. 0.52 g (2 mmol) of (+/−)2-iodomethyl-2,3-dihydro-benzofuran (prepared according to Synthesis 1997, (1), 23-25) in 2 ml of anhydrous dimethylformamide was added and the reaction mixture stirred at 60° C. for 20 min. The solution was treated with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol/ammonia in the proportions 99/1/0.1 to 98/2/0.2 to give 0.171 g of pure product obtained in the form of free base. Mp: 147-149° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH3:18])[N:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:7]=1)=[O:5])C.[CH2:29]([Mg]Br)[CH3:30]>C1COCC1.[Cu](I)I>[CH3:1][O:3][C:4]([CH:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH3:18])[N:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:7]1[CH2:29][CH3:30])=[O:5]
Reactant: CCOC(=O)c1cn(C(=O)OCc2ccccc2)c2c(C)nc(C)cc2c1=O
Reactant: CC[Mg]Br
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CCC1C(C(=O)OC)C(=O)c2cc(C)nc(C)c2N1C(=O)OCc1ccccc1

Procedure:
This compound can be obtained by reacting a stirred suspension of 6,8-dimethyl-4-oxo-4H-[1,7]naphthyridine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester, prepared in step (iii) and CuI (copper iodide) in THF, with freshly prepared EtMgBr (ethyl magnesium bromide) at −78° C., followed by a typical workup.
Reaction SMILES: [H-].[Na+].[Cl-].[C:4]([CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:5].[F:26][C:27]1[CH:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][N:28]=1.CO>O1CCCC1.CN(C)C=O>[F:26][C:27]1[CH:32]=[C:31](/[CH:33]=[CH:6]\[C:4]#[N:5])[CH:30]=[CH:29][N:28]=1
Reactant: O=Cc1ccnc(F)c1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: N#C/C=C\c1ccnc(F)c1
Reaction time: 48 h

Procedure:
To a suspension of 2.80 g (0.038 mol) sodiumhydride (60% in oil) in 120 ml tetrahydrofurane and 120 ml dimethylformamide were added 21.6 g (0.064 mol) (cyanomethyl)triphenyl-phosphonium chloride. After stirring for 1 hour at room temperature a solution of 4.00 g (0.032 mol) 2-fluoro-4-pyridinecarboxaldehyde in 35 ml tetrahydrofurane were added and stirring was continued for 2 days. Then 30 ml methanol were added, the solvents were evaporated and the residue chromatographed on silicagel with ethylacetate/hexane 1/2 to yield 0.45 g (10%) (E)-and (Z)-3-(2-fluoro-pyridin-4-yl)-acrylonitrile as light yellow solid. MS m/e (%): 148 (M+, 100), 128 (43).