Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14](O)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:31][CH:28]4[CH2:30][CH2:29]4)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1
Reactant: NC1CC1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)O)C3)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NC2CC2)C3)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
A mixture composed of 4-amino-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxylic acid of Example 8 (80 mg), cyclopropylamine (0.029 mL), 1-hydroxybenzotriazole monohydrate (32 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg) and dehydrated N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and sequentially washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (dichloromethane-methanol) to obtain the title compound (30 mg, 34%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[CH3:12][CH2:13][O-:14].[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH2:13][CH3:12])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1
Reactant: CC[O-]
Reactant: Clc1nc(Cl)c2cscc2n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nc(Cl)nc2cscc12
Reaction time: 2 h

Procedure:
6.15 g (0.03 mole) of 2,4-dichloro-thieno[3,4-d]pyrimidine are suspended in 250 ml. of absolute alcohol at 0°C. Whilst agitating constantly a solution of 0.03 mole sodium ethylate in ethyl alcohol is added drop by drop. The speed of addition is regulated in such a manner that the temperature of the reaction medium is maintained at between 0° and 5°C. One obtains a clear solution in which a precipitate is gradually formed. When the addition is completed, the agitation is continued for a further 2 hours at ordinary temperature. The reaction mixture is then poured into 2 liters of iced water and the precipitate formed is filtered off, washed with water and then dried in vacuo. After recrystallization from toluene, 5.2 g of 2-chloro-4-ethoxythieno[3,4-d]pyrimidine are obtained (81% of theory). M.P. 136°-140°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([C:19]([CH3:21])=[CH2:20])=[CH:15][C:14]=3[O:22][C:23]([F:26])([F:25])[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=3[O:22][C:23]([F:25])([F:26])[F:24])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=C(C)c1cc(OC(F)(F)F)c2c(c1)C1CN(C(=O)OC(C)(C)C)CCN1C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(OC(F)(F)F)c2c(c1)C1CN(C(=O)OC(C)(C)C)CCN1C2=O
Reaction time: 2 h
Yield: 101 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-isopropenyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one (67 mg, 0.16 mmol) and 10% palladium on carbon (5 mg) in MeOH (3 mL) was added hydrogen (1 atm). The reaction was stirred for 2 h and then filtered. The filtrate was conc in vacuo to a colorless oil. The oil was purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to yield 67 mg of the desired product as a colorless oil. MS (ESI) 415 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1.O>O1CCCC1>[CH:1]1([CH2:4][O:5][C:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:12][S:11][N:10]=2)[CH2:3][CH2:2]1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1cncc(-c2nsnc2OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a solution of cyclopropylcarbinol (360 mg, 5 mmol) and sodium hydride (110 mg, 5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 400 mg (69%) of the title compound.
Reaction SMILES: C1(O[C:8](=[NH:12])[NH:9][C:10]#[N:11])C=CC=CC=1.[NH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][N:21]=[C:20]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[C:30]([CH3:42])[CH:29]=1>C(O)(C)C>[C:8]([NH:9][C:10]([NH:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][N:21]=[C:20]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[C:30]([CH3:42])[CH:29]=1)=[NH:11])#[N:12]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCN)cc34)cc2C)cn1
Reactant: N#CNC(=N)Oc1ccccc1
Solvent: CC(C)O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=N)NC#N)cc34)cc2C)cn1
Temperature: 85 °C
Yield: 51.2 %

Procedure:
A mixture of 2-phenyl-N-cyano-isourea (50 mg, 0.31 mmol) and [6-(3-amino-prop-1-ynyl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine (30 mg, 0.076 mmol) in isopropanol (3 mL) was heated at 85° C. in a sealed tube. The reaction was cooled to room temperature after 5 hours. Solvent was removed via rotovap. The residue was then purified by FCC to give the final product (18 mg, 51%) as a light yellow solid. MS ESI (+) m/z 463 (M+1) detected; 1H NMR (400 MHz, deuterated DMSO) □ 9.9 (s, 1H), 8.7 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 7.8 (m, 2H), 7.75 (m, 2H), 7.2 (m, 3H), 7.0 (m, 3H), 4.22 (m, 2H), 2.42 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14](O)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:16])[CH3:15]
Reactant: O=C1CCCc2c(O)cccc2N1
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2c1CCCC(=O)N2
Temperature: 25 °C
Yield: 87 %

Procedure:
A suspension of 1,3,4,5-tetrahydro-6-hydroxy-2H-1-benzazepin-2-one (500 mg, 2.82 mmol) in 2.5 mL each of pyridine and acetic acid was stirred at room temperature. Excess reagents were removed under reduced pressure and the residue was triturated with CH2Cl2 to give 540 mg (87%) of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-one; MS 219.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:14]=2[CH3:21])[C:8](=[O:22])[CH:7]=1.[Br:28]NC(=O)CCC(N)=O>C(#N)C>[Br:28][C:7]1[C:8](=[O:22])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:14]=2[CH3:21])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: NC(=O)CCC(=O)NBr
Reactant: C=Cc1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(C)c1
Solvent: CC#N
Product: C=Cc1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(C)c1

Procedure:
The title compound was prepared by reacting 4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2-methyl-4-vinylphenyl)pyridin-2(1H)-one (0.64 g, 1.74 mmol) with N-bromosuccinamide (0.325 g, 1.83 mmol) in acetonitrile (9 mL) at 0° C. using a similar procedure as described in step 3 of Example 465, to give 0.423 g (54.5% after recrystallization) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (app q, J=7.59 Hz, 1H), 7.48 (s, 1H), 7.42 (dd, J=8.21, 1.98 Hz, 1H), 7.33 (dt, J=10.00, 2.27 Hz, 1H), 7.17 (dt, J=8.51, 2.44 Hz, 1H), 7.13 (d, J=7.88 Hz, 1H) 6.74 (dd, J=11.29, 6.34 Hz, 1H), 6.67 (s, 1H), 5.88 (d, J=17.85, 1H), 5.32-5.30 (m, 2H), 1.92 (s, 3H), 1.88 (s, 3H). ES-HRMS m/z 446.0579 (M+H calcd for C22H19BrF2NO2, requires 446.0568).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([CH3:14])=[N:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([CH3:14])=[N:3]1
Reactant: Cc1nn(C)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1nn(C)c2ccc(N)cc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
To a solution of 307a (crude, 2.5 mmol) in ethanol (95%, 30 mL) was added NH2NH2 water (1.25 g, 25.0 mmol), Pd/C (100 mg) under nitrogen protection. The mixture was stirred at 50° C. for 1.5 h. It was then cooled to room temperature and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure and the residue was recrystallized from anhydrous ethanol (5 mL) to afford 307b as white solid (340 mg, 84% over two steps). MS-ESI: [M+H]+ 162.3
Reaction SMILES: [CH2:1]([C:8]1[C:13]([NH:14][NH2:15])=[N:12][CH:11]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OCC)(=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([C:8]1[C:13]2[N:12]([C:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:15][N:14]=2)[CH:11]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NNc1ncc(-c2cccnc2)nc1Cc1ccccc1
Product: CCOC(=O)Cc1nnc2c(Cc3ccccc3)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing 2-benzyl-3-hydrazino-6-(3-pyridyl)pyrazine with diethyl malonate there is obtained ethyl 8-benzyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, which is converted by basic saponification into the above acid, MS: 301 (M-CO2)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:13][C:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([CH3:12])[CH:10]=2)[CH:5]=[CH:6][N:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc2c(=O)[nH]ccc2cc1F
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2c(OCc3ccccc3)nccc2cc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
6-Fluoro-7-methyl-2H-isoquinolin-1-one (prepared as described in WO2007012421, 13.2 g, mmol) was dissolved in tetrahydrofurane (175 mL). After addition of silver carbonate (41.2 g), benzyl bromide (15.3 g) was added dropwise. The mixture was stirred overnight. The mixture was heated to 70° C. and another 3 mL of benzyl bromide were added. Heating was continued until no further conversion was observed. The mixture was taken up in ethyl acetate, filtered over celite, evaporated and the residue was taken up in little ethyl acetate. The formed precipitate was filtered off to give 3.0 g of (2). The mother liquor was concentrated and chromatographed on silica gel to yield another 8.6 g of (2). Rt=4.00 min (Method 2). Detected mass: 268.1 (M+H+).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(=O)(O)[O-].[Na+].[CH3:26][C:27]([CH3:31])=[CH:28][CH2:29]Br>CN(C)C=O>[CH3:26][C:27]([CH3:31])=[CH:28][CH2:29][N:15]1[CH2:16][CH2:17][C@@:6]23[C:5]4[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=[CH:1][C:14]=4[CH2:13][C@@H:12]1[C@@H:11]2[CH2:10][CH2:9][CH2:8][CH2:7]3
Reactant: CC(C)=CCBr
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CC=C(C)C)CC3
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a mixture of 1.8 g of (-)-1-(morphinan-3-yl)ethanone, 0.6 g of sodium bicarbonate and 25 ml of dimethylformamide, was added 1.0 g of dimethylallyl bromide. After the mixture had been heated at 50° for 16 hours, it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between 50 ml of methylene chloride and 30 ml of water. The methylene chloride solution was washed with water and dried over magnesium sulfate. Removal of the solvent gave 2.1 g (93%) of crude (-)-1-[17-(3-methyl-2-butenyl)morphinan-3-yl]ethanone. For analysis, a sample of this compound was distilled, bp 185°-195° (0.05 mm), [α]25D-76.53° (c 0.98, MeOH).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](OCC2C=CC=CC=2)=[O:18])=[CH:13][C:12]=1[CH2:27][CH2:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[NH:2][CH3:1])=[CH:13][C:12]=1[CH2:27][CH2:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(CCCc2cc(C(=O)OCc3ccccc3)ccc2OCc2ccccc2)cc1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)O)cc2)c1
Temperature: 100 °C

Procedure:
To a 33% solution (16 ml) of methylamine in ethanol was added 4-[3-(2-benzyloxy-5-benzyloxycarbonylphenyl)propyl]benzoic acid (1.25 g). The mixture was heated at 100° C. for 12 hours in an autoclave. The solvent was evaporated and the residue extracted with ethyl acetate (100 ml) and washed with 1N aqueous HCl (100 ml) , dried (MgSO4), filtered and evaporated. The residue was subjected to chromatography on silica gel, eluting with EtOAc. The title product was purified by trituration with diethyl ether (150 mg) mpt. 163°-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[NH:7][C:6]=2[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][Si:27]([CH2:30][CH2:31][O:32][CH2:33]Cl)([CH3:29])[CH3:28]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:16]([F:17])([F:19])[F:18])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[N:7]([CH2:33][O:32][CH2:31][CH2:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:6]=2[CH:15]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OCCCCc1nc2cc(C(F)(F)F)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(CCCCO)nc2cc(C(F)(F)F)c(Cl)cc21
Reaction time: 1 h
Yield: 58.3 %

Procedure:
4-[6-chloro-5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]butan-1-ol (5.88 g, 20.09 mmol) was dissolved in DMF (50 ml) and anhydrous potassium carbonate (3.47 g, 25.11 mmol) was added at r.t. under N2 and the reaction stirred for 1 hr. SEM-Cl (3.92 ml, 22.10 mmol) was added and the reaction stirred for 3 hrs. The reaction mixture was concentrated in vacuo, EtOAc (150 ml) was added and the mixture was washed with 50% sat. brine solution (3×200 ml). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography eluting with MeOH:DCM (1:99-6:94) to give the product as a light orange oil (4.95 g, 58%): MS (ESI+) for C18H26ClF3N2O2Si m/z 424.40 [M+H]+; LC purity 81% (ret. time, 2.41 min); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm −0.11-0.01 (9H, m), 0.66-1.12 (2H, m), 1.60-1.87 (2H, m), 2.07 (2H, td, J=7.33, 2.05 Hz), 2.91-3.21 (2H, m), 3.43-3.61 (2H, m), 3.70 (2H, d, J=4.10 Hz), 5.49 (2H, d, J=17.81 Hz), 7.45-8.15 (2H, m)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][C:11]1[O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:8][CH:7]=2)=[N:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1ccc(C2=NCCO2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2ncc(Br)o2)cc1
Yield: 49.8 %

Procedure:
The above solution of 2-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole (4.8 g, 22 mmol), NBS (11.9 g, 66.9 mmol), and AIBN (0.18 g, 1.12 mmol) in CCl4 (200 mL) was refluxed for 16 h. The resulting solution was filtered and the filtrate was washed with aqueous 10% Na2S2O3 (3×150 mL), brine (100 mL), dried (Na2SO4), and concentrated. The resulting residue was recrystallized from hexanes (350 mL) to provide 3.2 g of 5-bromo-2-(4-(trifluoromethyl)phenyl)oxazole as a crystalline solid. The filtrate and mother liquor was concentrated and purified by flash chromatography over (SiO2, 100:0-90:10 hexanes-EtOAc). to furnish an additional 1.8 g: LCMS (m/z): 294.0 (MH+), tR=1.14 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23](O)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33][CH2:32]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:34]3[CH2:33][CH2:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=4)[CH2:35]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Reactant: COc1ccc2c(c1)CCNC2
Agent: Cl
Product: COc1ccc2c(c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccccc13)C2
Yield: 57.1 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 91 (57.1% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.86 and 3.03 (2t, 2H), 3.51 and 4.04 (2t, 2H), 3.72-3.78 (m, 6H), 3.87 and 3.92 (2s, 6H), 4.43 and 4.94 (2s, 2H), 6.65-7.27 (m, 3H), 7.68-8.18 (m, 6H); MS (ESI) m/z 486 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>C1COCC1>[Cl:11][CH2:12][CH2:13][C:14]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:15]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Product: O=C(CCCl)Nc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 3-nitroaniline (37a, 6.9 g, 50 mmol) in THF (50 mL) was added dropwise 3-chloropropionyl chloride (10 mL, 100 mmol) over 30 min under argon atmosphere. The reaction was stirred at 50° C. for 10 h. After cooling, the reaction mixture was evaporated to dryness under vacuo and the residue was neutralized with saturated aqueous solution of NaHCO3 and the solid product was collected by filtration, washed with water followed by hexane, and dried to afford 3-chloro-N-(3-nitrophenyl)propanamide, 10.61 g (92%), mp 86-88° C. (Lit. 100-102° C.57). 1H NMR (DMSO-d6) δ: 2.87-2.90 (2H, t, J=9.9 Hz, CH2), 3.90-3.92 (2H, t, J=9.9 Hz, CH2), 7.61-7.64 (1H, t, J=6.6 and 6.6 Hz, Ar—H), 7.90-7.94 (2H, m, Ar—H), 8.65-8.66 (1H, t, J=3.4 and 1.7 Hz, Ar—H), 10.59 (1H, brs, NH).
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=[O:8])[N:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[C:5](=[O:22])[NH:4]1)[CH3:2].Cl.C(OCC)C>O1CCOCC1>[CH2:1]([CH:3]1[NH:4][C:5](=[O:22])[N:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:7]1=[O:8])[CH3:2]
Reactant: CCC1NC(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCC1NC(=O)N(C2CCNCC2)C1=O
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl 4-(4-ethyl-2,5-dioxoimidazolidin-1-yl)piperidine-1-carboxylate (1.12 g) in dioxane (10 ml) was added a solution of 4M HCl in dioxane (10 ml) and the resulting mixture was stirred for 1 hour. Diethyl ether (20 ml) was added and the mixture was filtered and washed with diethyl ether to give 5-ethyl-3-piperidin-4-ylimidazolidine-2,4-dione. Yield 687 mg. MS 212 MH+
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22]([O:26]CC)(=[O:25])[CH:23]=[CH2:24].[OH-].[Na+]>CO>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:24][CH2:23][C:22]([OH:26])=[O:25])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Yield: 108.4 %

Procedure:
A mixture of 146 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 73.0 g of ethyl acrylate and 500 ml of methanol was refluxed for 1 hr and then 675 ml of 2N sodium hydroxide aqueous solution was added to the reaction mixture. The reaction mixture was refluxed for 1 hr and concentrated. Water was added to the residue and adjusted to pH 4 with hydrochloric acid. The precipitate was collected by filtration to give 200 g of colorless crystals, which were recrystallized from a mixture of water and N,N-dimethylformamide to give 198 g of colorless crystals. This compound was identified by comparing its mp, IR spectrum and NMR spectrum with those of the compound of Example 21.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1([C:16](=[NH:19])[NH:17][OH:18])[CH2:11][CH:10]1[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:21](C1NC=CN=1)(C1NC=CN=1)=[O:22]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1([C:16]2[NH:19][C:21](=[O:22])[O:18][N:17]=2)[CH2:11][CH:10]1[CH2:12][CH:13]([CH3:14])[CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(=N)NO
Solvent: C1CCOC1
Product: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)c1noc(=O)[nH]1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a solution of [1-(N-hydroxycarbamimidoyl)-2-isobutyl-cyclopropylmethyl]-carbamic acid tert-butyl ester (5.6 g, 19.6 mmol) in dry THF (190 mL) was added dropwise a solution of carbonyl diimidazole (4.8 g, 29.4 mmol) in dry THF (190 mL). The reaction mixture was heated to reflux for 12 hours and allowed to cool to room temperature. Excess of solvents was removed in vacuo and the residue was partitioned between ether (100 mL) and 1N NaOH (100 mL) solution. The ethereal solution was extracted with 1N NaOH (2×50 mL) and the combined aqueous layers were acidified to pH=3 with 4N HCl solution. The aqueous solution was extracted with EtOAc (3×100 mL) and the combined organic phase was washed with brine and dried over Na2SO4. Removal of excess of solvent, followed by purification of the residue by flash column chromatography using hexanes/EtOAc (1:1) as an eluent gave 4.66 g (76%) of {2-isobutyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclopropylmethyl}-carbamic acid tert-butyl ester as a colorless foam: 1H NMR (300 MHz, CD3OD) δ 0.89 (t, J=5.7 Hz, 1H), 0.96 (d, J=5.1 Hz, 3H), 0.98 (d, J=5.1 Hz, 3H), 1.26-1.37 (m, 3H), 1.43 (s, 9H), 1.63-1.71 (m, 2H), 3.35 (d, J=14.8 Hz, 1H), 3.53 (d, J=14.8 Hz, 1H); MS (APCI) m/z 210 [M+H-100(Boc)]+.