Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:20][CH3:21])([CH3:19])[C:16](O)=[O:17])[N:13]=2)=[N:6][CH:7]=1.C[N:30]1[CH2:35][CH2:34]O[CH2:32][CH2:31]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.N1CCCC1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:20][CH3:21])([CH3:19])[C:16]([N:30]3[CH2:35][CH2:34][CH2:32][CH2:31]3)=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: CN1CCOCC1
Reactant: COC(C)(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: ClCCl
Product: COC(C)(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
In a 20 mL scintillation vial, 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoic acid (0.087 g, 0.187 mmol) was dissolved in CH2Cl2 (5 mL) and DMF (2 mL) and N-methylmorpholine (0.031 mL, 0.281 mmol), followed by addition of 1-hydroxybenzotriazole. The mixture was cooled to 0° C. and EDCI (0.0467 g, 0.244 mmol) was added. The resulting mixture was agitated for 30 minutes and pyrrolidine (0.020 g, 0.28 mmol) was added. The mixture was then agitated overnight, diluted with 50 mL of CH2Cl2 and washed with citric acid solution and sodium bicarbonate solution, dried and evaporated to give crude product which was purified by chromatography on silica gel, eluting with 50-70% ethyl acetate/Hexane, to provide the title compound (0.079 g, 79% yield) as white solid. 1H NMR (DMSO-d6 δ 1.23 (s, 3H), 1.66-1.80 (m, 4H), 3.03-3.63 (m, 9H), 7.01 (m, 1H), 7.16-7.46 (m, 7H), 8.25 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:43][NH2:44]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:43][NH:44]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: COc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)cc1
Temperature: 150 °C
Yield: 11.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-[4-(methyloxy)phenyl]-3-piperidinecarboxamide (190 mg, 0.426 mmol), 3 mL of EtOH, Hunig's base (0.223 mL, 1.28 mmol), and hydrazine anhydrous (0.053 ml, 1.702 mmol) were added, and the yellow mixture was heated to 150° C. for 180 minutes in microwave. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH at 50° C., and EtOAc was used to triturate. When the solution turned slightly cloudy, it was cooled to room temperature to get pure crystallized light yellow title compound (22 mg). LC-MS (ES) m/z=459 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.46 (m, 1H), 1.65-1.84 (m, 2H), 1.98 (m, 1H), 2.79-3.06 (m, 2H), 3.72 (s, 3H), 4.49 (m, 1H), 4.68 (m, 1H), 5.37 (s, 2H), 6.10 (s, 2H), 6.68 (s, 1H), 6.88 (d, J=9.1 Hz, 2H), 7.53 (d, J=9.1 Hz, 2H), 7.58-7.65 (m, 1H), 7.66-7.78 (m, 1H), 7.97 (s, 1H), 9.87 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:42])([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)CCN2CCOCC2)cn3COCC[Si](C)(C)C)cc(OC)c1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)CCN4CCOCC4)c3n2)cc(OC)c1OC
Reaction time: 16 h
Yield: 74.7 %

Procedure:
A solution of 2,2-dimethyl-4-morpholin-4-yl-1-[2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butan-1-one (0.024 g, 0.040 mmol) in 1 mL of dichloromethane and 0.5 mL of trifluoroacetic acid was stirred for 3 h, then concentrated. The resulting residue was dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.054 g, 0.40 mmol). The mixture was stirred for 16 h, then concentrated to a residue. Column chromatography (0→10% MeOH/CH2Cl2) afforded 0.014 g (75%) of 2,2-dimethyl-4-morpholin-4-yl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butan-1-one as a brown solid.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([O:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:27](OB(O)O)=[C:26]([O:32][CH3:33])[CH:25]=[C:24]([O:34][CH3:35])[CH:23]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O>[CH3:35][O:34][C:24]1[CH:25]=[C:26]([O:32][CH3:33])[CH:27]=[C:22]([CH3:21])[C:23]=1[C:2]1[N:7]2[N:8]=[C:9]([O:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Reactant: COc1cc(C)c(OB(O)O)c(OC)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1cc(C)c(-c2cccc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
After dissolving tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (300 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL), 6-methyl-2,4-dimethoxyphenylboric acid (258 mg), tetrakis (triphenylphosphine)palladium(0) complex (203 mg) and barium hydroxide octahydrate (415 mg) were added and the mixture was heated and stirred at 80° C. for 3 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (230 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a brown oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([O:13]S(C)(=O)=O)[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][C:45](O)=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[CH:34][C:33]=1[Cl:52]>CN(C=O)C.C(OCC)(=O)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:13][C@H:12]4[CH2:11][O:10][C@@H:9]5[C@@H:3]([O:2][CH3:1])[C@@H:4]([O:7][C@H:8]45)[O:5][CH3:6])=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[CH:34][C:33]=1[Cl:52]
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OS(C)(=O)=O)[C@H]1OC
Reactant: COc1cc2c(Nc3ccc(Br)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Br)c(Cl)c3)ncnc2cc1O[C@H]1CO[C@@H]2[C@@H](OC)[C@H](OC)O[C@@H]21
Temperature: 135 °C
Yield: 28 %

Procedure:
Methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β-D-glucofuranoside (314 mg, 1.1 mmol) was dissolved in DMF (3 mL). To this solution was added potassium carbonate (404 mg, 2.9 mmol) and 4-[(4-bromo-3-chlorophenyl)amino]-6-methyloxy-7-hydroxyquinazoline trifluoroacetate (280 mg, 0.59 mmol). The resulting mixture was heated at 135° C. for 18 h. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (15 mL), washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 2-7% methanol in 1:1 ethyl acetate:hexanes) to give methyl 3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-α-L-idofuranoside as a white solid, 181 mg, 28% yield. 1H NMR (400 MHz; Methanol-d4): 8.75 (s, 1H), 8.04-8.06 (d, 1H), 7.99 (s, 1H), 7.78-7.75 (d, 1H), 7.64-7.61 (d, 1H), 7.35 (s, 1H), 5.16-5.14 (d, 1H), 5.02 (s, 1H), 4.89 (br, 1H), 4.69-4.68 (d, 1H) 4.46-4.42 (dd, 1H), 4.09 (br, 1H), 4.06 (s, 3H), 3.69(s, 1H), 3.48(s, 3H), 3.42 (s, 3H); MS (EI) for C23H23BrClN3O6: 551.88 (MH+).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[S:37]([NH-:40])(=[O:39])=[O:38].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC(O)=O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3/[CH:27]=[CH:28]/[C:29]([NH:40][S:37]([C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)(=[O:39])=[O:38])=[O:30])[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C/c1ccccc1-c1cccc(-c2ccccc2OCc2ccccc2)c1
Reactant: [NH-]S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1-c1cccc(-c2ccccc2OCc2ccccc2)c1)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.1 %

Procedure:
To (E)-3-(2-{3-[2-(Phenylmethoxy)phenyl]phenyl}phenyl)prop-2-enoic acid (210 mg, 0.52 mmol) of Example 2 (step 2), 2-thiophenesulfonylamide (121 mg, 0.74 mmol) and DMAP (250 mg, 2.04 mmol) in CH2Cl2 (3 mL) was added EDCI (142 mg, 0.74 mmol). After stirring at r.t. for 2 days, the reaction mixture was poured into 1N HCl (or aqueous AcOH) and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Purification by flash chromatography (Tol:EtOAc:AcOH, 1:0:0 to 20:1:0.1) and recrystallization (Hex:CH2Cl2) provided the desired material as a white solid (161 mg, 56%). 1H NMR (acetone-d6) δ 5.13 (2H, s), 6.72 (1H, d), 7.04 (1H, td), 7.1-7.2 (2H, m), 7.2-7.4 (8H, m), 7.4-7.5 (4H, m), 7.55 (1H, t), 7.62 (1H, dt), 7.7-7.8 (3H, m) and 7.92 (1H, dd).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])NC2SC(SCC(O)=O)=CN=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=O)CCCCC1.CC(C)CCN.C([O:44][C:45](=[O:56])[C:46]([S:49][C:50]1[S:54][C:53]([NH2:55])=[N:52][CH:51]=1)([CH3:48])[CH3:47])C>>[CH:1]1([N:7]([CH2:21][CH2:22][CH:23]([CH3:28])[CH3:24])[C:8](=[O:20])[NH:55][C:53]2[S:54][C:50]([S:49][C:46]([CH3:47])([CH3:48])[C:45]([OH:44])=[O:56])=[CH:51][N:52]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CCN
Solvent: O=C1CCCCC1
Product: CC(C)CCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from cyclohexanone, 3-methylbutylamine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: N1C=CC=[CH:3][C:2]1=O.[N+:8]([C:11]1[C:12]([OH:18])=[N:13][CH:14]=[CH:15][C:16]=1[OH:17])([O-:10])=[O:9].[H-].[Na+].C(I)C>CN(C=O)C>[CH2:2]([N:13]1[CH:14]=[CH:15][C:16]([OH:17])=[C:11]([N+:8]([O-:10])=[O:9])[C:12]1=[O:18])[CH3:3]
Reactant: O=c1cccc[nH]1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCn1ccc(O)c([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
1-Ethyl-4-hydroxy-3-nitro-1H-)pyridin-2-one: To a solution of 3-nitro-pyridine-2,4-diol (1.0 g, 6.41 mmol) in DMF (10 mL) at 0° C., was added NaH (0.51 g, 12.82 mmol 60% in mineral oil). After stirring at 0° C. for 15 min, ethyl iodide (1.10 g, 7.05 mmol) was added and the reaction was stirred at 55° C. for 17 h. After cooling to room temperature, the mixture was poured into ice water, and then filtered to remove insoluble material. The filtrate was acidified with 1 N HCl, extracted with CH2Cl2, dried with MgSO4, and concentrated. The product was rinsed with EtOH to give 1-ethyl-4-hydroxy-3-nitro-1H-pyridin-2-one (0.63 g, 53% yield). 1H-NMR (DMSO): 8, 7.79 (d, 1H, J=7.6 Hz), 6.09 (d, 1H, J=7.6 Hz), 3.90 (q, 2H, J=7.2 Hz), 1.19 (t, 3H, J=7.2 Hz).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[C:4]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.S(Cl)([Cl:23])=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:23][CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[C:4]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
Reactant: O=S(Cl)Cl
Reactant: O=C1NCC(CO)C1(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1NCC(CCl)C1(c1ccccc1)c1ccccc1

Procedure:
To 30.0 g. (0.11 mole) of 4-(hydroxymethyl)-3,3-diphenyl-2-pyrrolidinone in 200 ml. of chloroform was added 25.0 g. (0.20 mole) of thionyl chloride. To this stirring solution was added dropwise with ice bath cooling 20.0 g. (0.26 mole) of dry pyridine maintaining room temperature. The solution was refluxed for 2.5 hours. Upon cooling, the chloroform solution was washed successively with dilute hydrochloric acid solution and dilute sodium hydroxide solution. The chloroform was dried, filtered and concentrated in vacuo. The solid residue was recrystallized twice from ethyl acetate-isopropanol to give product melting at 218°-219° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH:23][S:28]([CH2:27][CH2:26][O:25][CH3:24])(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Reactant: COCCS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCCS(=O)(=O)Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (2.71 g, 8.84 mmol) stirred in pyridine (25 ml) at 0° C. was charged with 2-methoxy-ethanesulfonyl chloride (2.1 g, 13.26 mmol) dropwise causing a color change from yellow to bright orange. The reaction was allowed to warm to room temperature gradually and stirred 18 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 solution (100 mL). The aqueous layer was extracted with CH2Cl2 (2×50 ml) and the organic layer was concentrated to an oil. This was dissolved in EtOAc which caused an oil to separate. The EtOAc layer was separated and washed with saturated aqueous NaHCO3 solution (100 mL). The aqueous layer was extracted with EtOAc (2×50 ml) and the combined organic layer was washed with saturated aqueous NaCl solution (50 ml), dried over Na2SO4, filtered and concentrated to a crude orange liquid (3.77 g, ˜100%). (TLC 75% EtOAc/hexanes Rf 0.48);
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)=[O:17].Br[CH2:25][C:26]([NH2:28])=[O:27].ClCCl>CO>[NH3:3].[NH2:28][C:26]([CH2:25][N:21]1[CH2:22][CH2:23][C@H:19]([NH:18][C:16]([C@@H:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:17])[CH2:20]1)=[O:27]
Reactant: NC(=O)CBr
Reactant: O=C(N[C@H]1CCNC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Solvent: ClCCl
Solvent: CO
Product: N
Product: NC(=O)CN1CC[C@H](NC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)C1

Procedure:
The title compound was prepared by a similar method to Example 5 from (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-pyrrolidin-3-yl]-2-piperidinecarboxamide [see Example 4] and 2-bromoacetamide. The crude product was purifies by column chromotography on silica gel eluting with a solvent gradient of 93:7:1, changing to 90:10:1, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution to afford (2S)-N2-[(3S)-1-((aminocarbonyl)methyl)pyrrolidin-3-yl]-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.CC(C)=O.[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>O>[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:26])([O-:21])=[O:20]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccccn1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccn1)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a mixture of 2-aminopyridine (28.2 g), triethylamine (45 ml) and acetone (600 ml), 3-nitrobenzoyl chloride (55.8 g) was gradually added with stirring under ice cooling. The mixture was stirred for 30 minutes under the same condition, then for one hour at room temperature. Thereafter, the reaction solution was poured into 3 liters of water, and the resulting crystal was collected by filtration, washed with water, and recrystallized from methanol to provide 58.5 g of 3-nitro-N-2-pyridylbenzamide as a colorless acicular crystal (yield: 80%, m.p. 156°-157° C.). Hydrogen was bubbled into a mixture of the 3-nitro-N-2-pyridylbenzamide (15.9 g), 10% palladium-carbon (1.5 g) and ethanol (300 ml). After a stoichiometric amount of hydrogen was absorbed, the catalyst was removed, the reaction mixture was concentrated under vacuum, and the residue was recrystallized from ethanol to provide 7.2 g of a colorless acicular crystal of 3-amino-N-2-pyridylbenzamide (yield: 52%, m.p. 113°-115° C.). To a mixture of the 3-amino-N-2-pyridylbenzamide (6.4 g), triethylamine (4.5 ml) and acetone (60 ml), propionic acid chloride (2.8 g) was gradually added with stirring at room temperature. After one hour of stirring, the reaction mixture was poured into 200 ml of water which was then made weakly alkaline by gradually adding a 10% solution of sodium hydroxide. The resulting crystal was collected by filtration, washed with water and recrystallized from methanol to provide 7.0 g of 3-propionyl-N-2-pyridylbenzamide as a colorless acicular crystal (compound 1) (yield: 87%, m.p. 128°-129° C.).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6]CC)=O.Br[CH:14]([CH3:16])[CH3:15].[NH2:17][C:18]([NH2:20])=[O:19]>C(O)C.CO.O.Cl>[CH:14]([CH:3]1[C:2](=[O:10])[NH:20][C:18](=[O:19])[NH:17][C:4]1=[O:6])([CH3:16])[CH3:15]
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)Br
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC(C)C1C(=O)NC(=O)NC1=O
Temperature: 80 °C
Yield: 43.4 %

Procedure:
Sodium metal (1.28 kg, 55.65 mol) was dissolved in ethanol (25 L) under nitrogen atmosphere at 0° C. (bath temperature). Diethyl malonate (7.45 kg, 46.51 mol) was added to the solution and the mixture was heated to 80° C. 2-Bromopropane (8.00 kg, 65 mol) was added dropwise to the solution for 1 hour, and the solution was refluxed for 10 hours. The solution was cooled to room temperature. Sodium metal (1.22 kg, 53.04 mol) was dissolved into the solution under nitrogen atmosphere at 0° C. Urea (2.78 kg, 46.28 mol) in methanol (15 L) was added to the solution over 2 hours and the reaction mixture was refluxed for 20 hours. The reaction mixture was diluted with water (35 L) and conc. HCl (5 L), and cooled to room temperature. The precipitate was collected by filtration, washed with water (20 L), ether (15 L), n-hexane (20 L) and dried in vacuum at 40° C. for 10 hours to give 5-isopropylbarbituric acid as a white solid (3.42 kg, 20.10 mol, 43% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:36])([CH3:35])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:25]2[CH2:24][CH2:23][N:22]([C:18]3[CH:17]=[C:16]([CH:11]4[C:10]([CH3:36])([CH3:35])[CH2:9][C:8]5[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=5)[NH:12]4)[CH:21]=[CH:20][CH:19]=3)[CH2:27][CH2:26]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(c4ccc(Cl)cc4)CC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCN(c3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 52.5 %

Procedure:
A mixture of 2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.20 g, 0.40 mmol), lithium hydroxide hydrate (167 mg, 4.0 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 53%) as a white solid: LC/MS m/e calcd for C28H30ClN3O2 M+: 476.02, observed: 476.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=1.[CH2:15]([Cl:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[ClH:22].[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)cc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)c(N2CCOCC2)c1
Product: Cl

Procedure:
A well stirred mixture of 4-bromo-2-morpholino phenol (4.44 g, 0.017 mole), benzyl chloride (2.3 ml, 0.02 mole), potassium carbonate (4.75 g, 0.034 mole), and dry acetone (60 ml) was heated under reflux for 7 hours. The mixture was diluted with water, extracted with ether and the combined extracts washed with dilute sodium hydroxide solution and with water. Extraction of the ethereal solution with concentrated hydrochloric acid and evaporation of these extracts under reduced pressure gave 4-benzyloxy-3-morpholinobromobenzene hydrochloride, which was collected and washed with ether (5.29 g, 80%, m.p. 164°-174°C). The hydrochloride, recrystallised from ethanol, had m.p. 168°-177°C. A suspension of the hydrochloride in water was treated with excess potassium carbonate and 4-benzyloxy-3-morpholinobromobenzene extracted into ether. Evaporation of the ether extracts gave the free base, m.p. 84°-87°C.