Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]([CH3:47])([CH2:45]C)[C:10]([NH:12][C@@H:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH2:37][NH:38][C:39]([NH:41][CH3:42])=[O:40])=[CH:27][C:26]=2[Br:43])[C:14]1=[O:44])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:8][C:9]([CH3:47])([CH3:45])[C:10]([NH:12][C@@H:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH2:37][NH:38][C:39]([NH:41][CH3:42])=[O:40])=[CH:27][C:26]=2[Br:43])[C:14]1=[O:44])=[O:11]
Reactant: CCC(C)(NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)NC)cc2Br)C1=O
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)N)CCc3ccccc32)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 146 mg (0.211 mmol) of 2-t-butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(methylamino)carbonyl]amino]methyl]-3-bromo-[1,1'-biphenyl]-4-yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step L) in 5 L of methylene chloride was added 5 drops of anisole followed by 5 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 hour then the solvent was removed under vacuum. The residue was purified by reverse phase medium pressure liquid chromatography on C-8, eluting with methanol/0.1% aqueous trifluoroacetic acid (60:40), to afford 87 mg (58%) of the title compound as a white solid. 1H NMR (200 MHz, CD3OD): δ 1.52 (s, 3H), 1.59 (s, 3H), 2.32 (m, 2H), 2.60-3.02 (m, 2H), 2.65 (s, 3H), 4.17 (dd; 18, 14 Hz; 2H), 4.43 (dd; 12, 9 Hz; 1H), 4.90 (d, 16 Hz, 4H), 5.34 (d, 16 Hz, 2H), 7.10-7.42 (m, 8H), 7.50 (m, 3H). FAB-MS: calculated for C30H34BrN5O3 592; found 593, 595 (100%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)C=C[C:2]=1C(C)C(O)=S.[CH:16]1[CH:17]=[CH:18][C:19]2N(O)N=[N:22][C:20]=2[CH:21]=1.O.O1CCCC1>CN(C)C=O>[CH2:17]1[CH2:16][CH2:21][CH:20]([N:22]=[C:2]=[N:1][CH:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:19][CH2:18]1
Reactant: On1nnc2ccccc21
Reactant: CC(C(O)=S)c1ccc2ccccc2n1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1A using 1.8 g (5.2 mmol) of the subtitled compound of Preparation 1D, 1.8 g (5.2 mmol) of (2S)-2-N(t-butoxycarbonyl)amino-4-(quinolin-2-ylthiopropanoic acid, 0.70 g (5.2 mmol) of HOBT.H2O and 1.1 g (5.2 mmol) of DCC, in a 15 mL of tetrahydrofuran containing 2 mL of dimethylformamide, to provide 3.1 g of a yellow solid. This solid was purified using flash chromatography (eluent of 35% ethyl acetate in toluene) to provide 1.8 g of a white solid. Yield: 51%. 1H NMR (CDCl3): δ1.40 (s, 9 H), 1.45 (s, 9 H), 2.95 (m, 4 H) , 3.57 (d, J=4 Hz, 2 H), 3.65 (m, 1 H), 4.30 (m, 1 H), 4.52 (q, J=5 Hz, 1 H), 6.02 (br.s, 2 H), 6.85 (d, J=9 Hz, 1 H), 7.10-7.38 (m, 10 H), 7.46 (t, J=7 Hz, 1 H), 7.70 (m, 2 H), 7.90 (d, J=9 Hz, 1 H), 8.04 (d, J=8 Hz, 1 H). MS (FD): m/e 670 (M+). IR (KBr): 3292, 1715, 1637, 1594, 1518 cm-1. UV (EtOH): 210 nm (E=58,247), 257 nm (E=23,586), 327 nm (E=5,628), 339 nm (E=6,082).
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:8]1[N:9]=[C:10]([CH2:13][N:14]2[N:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[N:15]2)[O:11][CH:12]=1)([CH3:7])[CH3:6].[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][C:5]([C:8]1[N:9]=[C:10]([CH2:13][N:14]2[N:18]=[C:17]([NH2:19])[CH:16]=[N:15]2)[O:11][CH:12]=1)([CH3:7])[CH3:6]
Reactant: COC(C)(C)c1coc(Cn2ncc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COC(C)(C)c1coc(Cn2ncc(N)n2)n1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 4-(2-methoxypropan-2-yl)-2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)oxazole (56 mg, 0.21 mmol), iron powder (35 mg, 0.63 mmol) and NH4Cl (57 mg, 1.05 mmol) in a mixture of EtOH (1.0 mL) and water (0.5 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (2 mL) was added followed by 1N NaOH (2 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (2 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 06: tR=0.46 min; [M+H]+=238.09.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[C:8]=2[C:7]1=[O:37].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>CCOC(C)=O>[NH2:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:11]1[N:10]=[C:9]([C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[C:8]2[C:7](=[O:37])[NH:6][CH2:14][C:13]=2[C:12]=1[F:15].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1

Procedure:
A solution of tert-butyl (1S,2R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (2.4 g, 4.04 mmol) and TFA (5 mL, 64.9 mmol) was stirred at 80° C. for 30 min. The resulting suspension was diluted with EtOAc (5 mL) and filtered. The filtrate was evaporated in vacuo. The residue was diluted with H2O (300 mL) and EtOAc (100 mL) and filtered. The precipitate was washed with EtOAc and dried to give the title compound as a TFA salt (900 mg). The filtrate was extracted with EtOAc (200 mL). The aqueous phase was neutralized with saturated aq NaHCO3 solution and extracted with EtOAc (2×400 mL) and THF (2×200 mL). The organic phases were combined, dried over MgSO4, and evaporated. The residue was washed with EtOAc to give a first crop (400 mg) of the title compound as the free base. The TFA salt obtained above was diluted with saturated aq NaHCO3 solution (20 mL) and stirred at RT overnight. The resulting suspension was filtered and the solids were washed with EtOAc to give a second crop (700 mg) of the title compound as the free base (1.1 g, 79%).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([C:56](O)=[O:57])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1.CN(C=O)C.O>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:56]([CH:53]4[CH2:54][CH2:55][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[CH2:51][CH2:52]4)=[O:57])[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Compound 140 (0.200 g, 0.55 mmol) was dissolved in THF-DMF (1:4)(5.0 mL), and EDC (0.138 g, 0.72 mmol), 1-hydroxybenzotriazole hydrate (89.2 mg, 0.66 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (151 mg, 0.66 mmol) were added to the solution, followed by stirring at room temperature overnight. The reaction mixture was added with water and extracted with ethyl acetate three times. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to obtain 4-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-ylmethyl)phenylamino]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylcarbonyl]piperidine (0.311 g, 0.54 mmol, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:36]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:43])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3cccnc3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, nicotinoyl chloride hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]([CH3:12])[N:4]=1.[CH3:13][OH:14]>[N+]([O-])([O-])=O.[Ag+]>[Cl:11][C:6]1[N:5]([CH3:12])[N:4]=[C:3]([CH2:2][O:14][CH3:13])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CO
Reactant: Cn1nc(CBr)c([N+](=O)[O-])c1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: COCc1nn(C)c(Cl)c1[N+](=O)[O-]
Yield: 40 %

Procedure:
A solution of 3-bromomethyl-5-chloro-1-methyl-4-nitropyrazole (5.0 g, 19.6 mmol) in methanol (50 ml) was treated with silver nitrate (5.75 g, 33.8 mmol) and the mixture heated under reflux for 2 hours. The cooled reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml) and the aqueous phase extracted with a further quantity of ethyl acetate (50 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum. Chromatography on silica gel, eluting with a 97:3 mixture of dichloromethane and methanol, gave the title pyrazole as a white solid (1.6 g, 40%), m.p. 59-63° C. Found: C, 34.65; H, 3.83; N, 20.05. C6H8ClN3O3requires C, 35.05; H, 3.92; N, 20.44%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:15]([C:14]1[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2](/[CH:19]=[CH:18]/[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:3]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(I)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2ccncc2)c1
Temperature: 110 °C
Reaction time: 22 h
Yield: 39.1 %

Procedure:
A mixture of 2-(3-iodophenylamino)-3-nitropyridine (3.86 g), 4-vinylpyridine (1.78 g), palladium(II) acetate (80 mg), tetrabutylammonium chloride (3.14 g) and sodium bicarbonate (2.4 g) in N,N-dimethylformamide (20 ml) was stirred at 110° C. for 22 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (chloroform-methanol (50:1)) to give 3-nitro-2-[3-[(E)-2-(4-pyridyl)vinyl]phenylamino]pyridine (1.41 g) as an orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]3[CH:20]=[CH:21][O:22][C:18]=3[C:17]([F:23])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>ClCCl>[ClH:24].[F:23][C:17]1[C:18]2[O:22][CH:21]=[CH:20][C:19]=2[C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c3occc23)CC1
Agent: Cl
Solvent: ClCCl
Product: Fc1ccc(C2=CCNCC2)c2ccoc12
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
To a stirred solution of 4-(7-fluoro-benzofuran-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.97 g, 3.06 mmol) in dichloromethane (23 ml) was added at room temperature hydrochloric acid solution (4M in dioxane, 11.5 ml, 45.8 mmol) and the reaction mixture was allowed to stir for 1.5 h. The reaction mixture was evaporated, the residue triturated with diethyl ether (50 ml) and MeOH (1 ml), the precipitate was collected by filtration, washed with diethyl ether and dried to yield 4-(7-fluoro-benzofuran-4-yl)-1,2,3,6-tetrahydro-pyridine hydrochloride as light yellow solid (0.7 g, 90%), MS (ISP) m/z=218.2 [(M+H)+], mp 202° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH3:2].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][CH:41]=3)[C:36](O)=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[C:47]([O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C@H:35]([NH:34][C:32](=[O:33])[O:31][CH2:30][CH:28]2[C:29]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:36]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])[CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:37])=[CH:45][CH:44]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(CNCc1ccncc1)OCC
Product: CCOC(CN(Cc1ccncc1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 85.8 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, 2,2-diethoxy-N-(pyridin-4-ylmethyl)ethanamine (Compound IX-15) (70.8 g, 315 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (128.6 g, 280 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=1:1 to 0:100) to obtain the title compound (160.0 g, 76%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH3:5][C:6]1([CH3:14])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7]1=[O:13].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][C:8]([CH3:12])([C:9](=[O:10])[CH:6]([CH3:14])[CH3:5])[C:7]([O:3][CH2:2][CH2:1][OH:4])=[O:13]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)C(=O)C(C)(C)C(=O)OCCO
Reaction time: 1 h

Procedure:
To a 2-liter round bottom flask was charged ethylene glycol (800 mL) and 2,2,4,4-tetramethyl-1,3-cyclobutanedione (185.8 g, 1.33 moles). While using good mixing, potassium carbonate (91.4 grams, 0.663 moles) was added. An exothermic reaction resulted and the batch temperature rose to approximately 65° C. The reaction was held for 1 hour between 50-60° C. The batch was then drowned into 1300 mL demineralized water and extracted with 800 mL ethyl acetate. The ethyl acetate layer was washed several times with water and dried with anhydrous sodium sulfate. The ethyl acetate was removed at 75° C. under 5 mmHg vacuum and the resulting crude product distilled through a 0.5×6 inch Penn-State packed column to provide 153 g of distilled product. The vapor boiling point was recorded as 113° C. at a pot temperature of 135° C. at <1 mmHg vacuum. The GC assay of the resulting product was 97.2%.
Reaction SMILES: CN1C(=O)C(C)(N2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=3[F:19])[C:10]2=[O:23])C(=O)NC1=O.Cl.[NH2:28][C:29]1([CH2:40][CH3:41])[C:34](=[O:35])[N:33]([CH2:36][CH3:37])[C:32](=[O:38])[NH:31][C:30]1=[O:39]>>[CH2:36]([N:33]1[C:34](=[O:35])[C:29]([CH2:40][CH3:41])([N:28]2[C:10](=[O:23])[C:11]3[C:16](=[C:15]([F:19])[C:14]([F:20])=[C:13]([F:21])[C:12]=3[F:22])[C:17]2=[O:18])[C:30](=[O:39])[NH:31][C:32]1=[O:38])[CH3:37]
Reactant: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Reactant: CCN1C(=O)NC(=O)C(N)(CC)C1=O
Agent: Cl
Product: CCN1C(=O)NC(=O)C(CC)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O

Procedure:
Compound 19d was synthesized in the same manner as described for 19a from 5-amino-1,5-diethylbarbituric acid hydrochloride (0.35 g, 1.50 mmol). The crude product was recrystallized from EtOH (70%) to give 1,5-diethyl-5-(tetrafluorophthalimido)barbituric acid (19d) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.C(=O)(O)[O-].[Na+]>[Fe].C(O)C>[NH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([Br:1])[CH:12]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCOC(=O)c1ccc(N)cc1Br
Yield: 84.8 %

Procedure:
Ethyl 2-bromo-4-nitrobenzoate (46g; 0.17 mole), ethanol (250 ml), iron powder (28 g; 0.5 mole) and concentrated hydrochloric acid (20 ml) are successively introduced into a 1 liter flask. The mixture is taken to reflux temperature for four hours. After cooling, the reaction mixture is treated with a saturated solution of sodium bicarbonate (500 ml) and extracted with ethyl acetate (5×300 ml). After drying over magnesium sulphate, filtration and evaporation, ethyl 4-amino-2-bromobenzoate (35.2 g; yield:86%) is isolated, m.p. 93° C. (compound no. 254).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[N:19][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH2:29][CH:30]([OH:43])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C=O.O>[CH2:7]([C:15]1[CH:20]=[N:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:29][C@@H:30]([OH:43])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:23][CH:22]=2)=[N:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCOCCOCCOCC(O)CCl
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCc1cnc(-c2ccc(OC[C@@H](O)COCCOCCOCCCC)cc2)nc1
Temperature: 25 °C

Procedure:
Potassium carbonate (2.1 g, 15.7 mmol) was added to a solution of 5-octyl-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 10.5 mmol) and 1-chloro-3-(2-(2-butoxyethoxy)ethoxy)-2-propanol (2.7 g, 10.5 mmol) in N,N-dimethylformamide (100 ml). The resulting mixture was stirred at reflux temperature for 18 hours and then cooled to ambient temperature. The mixture was diluted with water (100 ml) and was extracted with three 100 ml aliquots of diethyl ether. The extracts were dried (over MgSO4), filtered, and concentrated to give crude product as an oil. 5-Octyl-2-[4-((S)-2-hydroxy-3-(2-(2-(butoxy)ethoxy)ethoxy)propoxy)phenyl]pyrimidine was then isolated by chromatography. The chiral (S)-hydroxy compound (3.5 g, 7.5 mmol) was treated with diethylaminosulfur trifluoride (5.3 g, 15 mmol) to produce Comparative Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>>[Cl:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(=O)CCl
Reactant: Nc1nccnc1Cl
Product: Cc1cn2ccnc(Cl)c2n1

Procedure:
For example, condensation of a 2-amino-3-chloropyrazine with chloroacetone gives an 8-chloro-2-methylimidazo[1,2-a]pyrazine as shown the following reaction Scheme II. ##STR14##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)[CH2:25][CH2:24]1
Reactant: ClCC1CC1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC2CC2)c1=O
Yield: 54.7 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 54.7%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=1)[CH2:2][O:1][C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1)#[N:9]
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cncc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:50]([O:52][C:53](=[O:56])[CH2:54][NH2:55])[CH3:51]>CN(C=O)C.O>[CH2:50]([O:52][C:53](=[O:56])[CH2:54][NH:55][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:26][CH:25]=1)[CH3:51]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
DIPEA (5.12 g, 6.85 mL, 0.59 mmol) was added to a stirred solution of 4-benzyloxy benzoic acid (2 g, 8.7 mmol) in DMF (18 mL). HOBT (1.3 g, 9.5 mmol) and EDCI.HCl (4.2 g, 21.7 mmol) were added at room temperature. After 2 minutes glycine ethyl ester HCl (1.47 g, 10.5 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 40% EtOAc in Hexane as eluent) afforded 2.47 g (90.1% yield) of (4-Benzyloxy-benzoylamino)-acetic acid ethyl ester. LCMS Purity %: 98.6, 1H NMR (DMSO): δ 8.9 (t, 1H), 7.8 (d, 2H), 7.5 (m, 5H), 7.2 (d, 2H), 5.4 (s, 2H), 4.2 (q, 2H), 4.0 (d, 2H), 0.8 (t, 3H).