Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([CH2:16]O)=[CH:11][C:10]=2[Cl:18])[C:5](=[O:19])[CH:4]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([CH2:16][F:28])=[CH:11][C:10]=2[Cl:18])[C:5](=[O:19])[CH:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=c1cc(C(F)(F)F)ccn1-c1c(Cl)cc(CO)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(C(F)(F)F)ccn1-c1c(Cl)cc(CF)cc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
A dry flask was flushed with nitrogen and charged with 4-trifluoromethyl-1-(2,6-dichloro-4-hydroxymethylphenyl)-2-pyridone (Compound D) [0.73 g (2.2 mmol)] and dry dichloro-methane (15 ml). The flask was cooled to -78° C. and diethylaminosulphurtrifluoride (0.31 ml, 2.4 mmol) was added slowly dropwise. The reaction was stirred at -78° C. for 2 hours and then slowly allowed to warm up to room temperature. The reaction was slowly added to a saturated solution of sodium hydrogen carbonate (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed well with water, dried over magnesium sulphate, and evaporated in vacuo to give a yellow solid which was chromatographed on silica with 50% petrol/diethyl ether as eluent. Recrystallisation from a mixture of pentane and diethylether gave 4-trifluoromethyl-1-(2,6-dichloro-4-fluoromethylphenyl)-2-pyridone (Compound 40) (0.18 g)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][OH:13])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(O)COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of 1-O-monobenzyl glycerol (1.58 g) in methylene chloride (20 ml), t-butyldimethylsilyl chloride (1.44 g) and then triethylamine (1.33 ml) and N,N-dimethylaminopyridine (0.04 g) were added, and the mixture was stirred overnight at room temperature. Methylene chloride (20 ml) was further added to the reaction liquid, and the mixture was washed with water (20 ml×3) and saturated ammonium chloride (20 ml×3), dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain pale yellow oil. The product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=7/1) to obtain the desired product (1.93 g) as pale yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([OH:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([O:18][C:25](=[O:27])[CH3:26])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)NC(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)OC(C)=O

Procedure:
The above ethyl 2-(benzyloxycarbonylamino)-2-(hydroxy)acetate (24.9 g), 34.2 ml of pyridine and 24.3 ml of acetic anhydride in 250 ml of tetrahydrofuran was stirred at room temperature for 30 minutes. It was then concentrated in vacuo, and dried under high vacuum for 4 hours to give 25.0 g of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([N:21]5[CH2:25][CH2:24][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]5)[N:19]=4)[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:36]I>O1CCCC1>[CH3:36][N:26]([C@@H:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:19]=[C:20]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:16][CH:17]=2)[CH2:22]1)[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a cooled (0° C.) solution of (R)-tert-butyl 1-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrrolidin-3-ylcarbamate (111 mg, 0.249 mmol) in tetrahydrofuran (2.0 mL) was added sodium hydride (60% dispersion in mineral oil, 15 mg, 0.37 mmol). After 30 minutes at 0° C., a solution of methyl iodide (23 uL, 0.37 mmol) in tetrahydrofuran (0.5 mL) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature as the ice bath melted, stirred overnight, then quenched by adding water (1.0 mL). The tetrahydrofuran was removed in vacuo and the remaining aqueous solution was diluted with ethyl acetate (100 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluting with chloroform/acetone (2-20%) to afford tert-butyl methyl{(3R)-1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-yl}carbamate (104 mg, 91%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1COCC1.CCOC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(CO)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(CO)c1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a chilled suspension of 3-aminobenzyl alcohol (9.24 g, 75 mmol) in THF (50 mL) was added neat acetic anhydride (8.1 mL, 86 mmol). The reaction mixture was stirred cold for 1 hr, diluted with EtOAc, washed with aq. NaOH and brine, and concentrated in vacuo to give N-[3-(hydroxymethyl)phenyl]acetamide (10.5 g, 85%).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:14]=2[O:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[O:12])/[N:7]([CH2:37][C@H:38]2[CH2:42][CH2:41][CH2:40][O:39]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:12])[C:13]2[CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][C:14]=2[O:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)/[N:7]([CH2:37][C@H:38]2[CH2:42][CH2:41][CH2:40][O:39]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H]2CCCN2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of Example 25A (440 mg, 0.72 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) and stirred at room temperature for 2 hours. The reaction was concentrated, taken up in dichloromethane and washed with saturated sodium bicarbonate solution. The aqueous layer was washed with dichloromethane. The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 gm particle size) using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-nm delay) to obtain the title compound (350 mg , 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9 H) 1.39-1.53 (m, 1 H) 1.57-1.69 (m, 1 H) 1.76-1.95 (m, 5 H) 2.40-2.46 (m, 1 H) 2.63-2.74 (m, 2 H) 2.80-2.89 (m, 2 H) 3.58-3.69 (m, 1 H) 3.75-3.82 (m, 1 H) 3.95-4.09 (m, 2 H) 4.18-4.31 (m, 3 H) 7.24-7.29 (m, 2 H) 7.74 (dd, J=8.92, 2.58 Hz, 1 H) 7.99 (d, J=2.38 Hz, 1 H); MS (DCI/NH3) m/z 512 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13](OC)=[O:14].[CH3:24][NH2:25].CO>CO>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([NH:25][CH3:24])=[O:14]
Reactant: COC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reactant: CN
Solvent: CO
Product: CNC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reaction time: 22 h
Yield: 82.1 %

Procedure:
A solution of methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl)-2-methoxyacetate (0.44 g, 1.40 mmol) in methanol (5 ml) was stirred at room temperature. 40% methylamine/methanol solution (0.33 g, 4.2 mmol) was added thereto. After 22 hours, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give the desired compound 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide (0.36 g, 82%) as white crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12][OH:13])=[O:6])[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.C1(C)C=CC=CC=1>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([O:13][CH2:12][C:11]2[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[N:9]=[N:8][C:7]=2[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])=[CH:28][CH:27]=1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Reactant: Oc1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a suspension of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (0.10 g) obtained in Example 112 in THF (3 ml)—toluene (3 ml) were added 4-bromophenol (0.053 g), tributylphosphine (0.15 ml) and ADDP (0.15 g). The reaction mixture was stirred at room temperature for 15 min, the insoluble material was filtered off, and the solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=1/2 to ethyl acetate). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (0.14 g, 95%).
Reaction SMILES: Cl[CH2:2][CH:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][O:4]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[Na+].[I-].Cl>CN(C=O)C.O>[S:11]1[C:7]2[CH2:6][CH2:5][O:4][CH:3]([CH2:2][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]=2[CH:9]=[CH:10]1
Reactant: ClCC1OCCc2sccc21
Reactant: C1CCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc2c(s1)CCOC2CN1CCCC1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(chloromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran (1 g, 5.305 mmol, 1 eq), pyrrolidine (11.3 g, 159.1 mmol, 30 eq) and NaI (50 mg) in DMF (50 mL) in a sealed tube was stirred at 130° C. for 6 hr. The reaction mixture was cooled and poured into H2O and the pH was adjusted to ˜2 with 2N HCl. The resulting solution was washed with EtOAc. The aqueous layer was then adjusted to pH 9-10 and extracted with EtOAc. The EtOAc layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by preparative HPLC. After removal of organic volatiles of the collected HPLC fractions, the pH of remaining aqueous phase was adjusted to ˜8 with saturated Na2CO3 solution. The aqueous solution was extracted with EtOAc (3 times). The combined EtOAc extract was washed with brine, dried with Na2SO4, and concentrated to give the desired product.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([CH2:19]Cl)=[CH2:18]>C(#N)C>[CH2:16]=[C:17]1[CH2:19][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:18]1
Reactant: C=C(CCl)CCl
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C1COc2ccccc2OC1
Temperature: 25 °C

Procedure:
Catechol (5.09 g, 46.2 mmol) and potassium carbonate were combined in acetonitrile and heated to reflux for one hour. 2-Chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol) was added and the reaction was continued at reflux for 24 hours. The solution was cooled to room temperature and filtered. The filtrate was evaporated and the residue was diluted with water and extracted with diethyl ether (3×). The combined organic solution was dried over MgSO4 and concentrated. Chromatography (2% ethyl ether in hexane) yielded 3-methylene-3,4-dihydro-2H-benzo[b][1,4]dioxepine as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=O>CO>[C:1]1([N:7]2[CH2:8][CH2:9][O:10][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: OCCNc1ccccc1
Solvent: CO
Product: c1ccc(N2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3POX A 500 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser, an addition funnel, and a heating mantle with power supply. The flask was charged with 137.17 g (1.0 mole) of N-phenylethanolamine (NPEA) and 25 g of methanol. The addition funnel was charged with 55.20 g of Formcel® (1.01 moles of formaldehyde). The NPEA solution was stirred at room temperature under a blanket of nitrogen, and the Formcel® was added over a period of 1.25 hours. After completing the addition, the reaction mixture was stirred at room temperature overnight. The bulk of the solvent was removed from the reaction mixture by rotary evaporation. Toluene was added to remove water as an azeotrope. The yield of 3POX was 144.54 g (97%) as a clear, amber oil. Product structure was confirmed by NMR and GC/MS analyses.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]=[N:10][CH2:11][CH2:12][CH3:13])[N:3]=1.[CH2:14](I)[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:13][CH2:12][CH2:11][N:10]([CH:9]=[N:8][C:4]1[NH:3][C:2](=[O:1])[CH:7]=[CH:6][CH:5]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCI
Reactant: CCCN=CNc1cccc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCN(C=Nc1cccc(=O)[nH]1)CCC

Procedure:
1.8 g (10 mmol) of N-(2-pyridon-6-yl)-N'-propylformamidine and N-(2-hydroxy-6-pyridyl)-N'-propylformamidine, 1.9 g (11 mmol) of propyl iodide and 1.5 g (11.mmol) of potassium carbonate are stirred at 80° for 24 hours in 30 ml of absolute ethanol. The reaction mixture is then filtered and concentrated by evaporation The residue is taken up in methylene chloride, washed with water and then dried over Na2SO4 and concentrated by evaporation. The resulting crude product is purified chromatographically. Crystallisation from methylene chloride/ether yields N-(2-pyridon-6-yl)-N',N'-di-n-propylformamidine and N-(2-hydroxy-6-pyridyl)-N',N'-di-n-propylformamidine having a melting point of 102°-104°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)C(C)Cc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Cc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step E was prepared from 2-methyl-3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step δ and benzenesulfonyl chloride, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine and with a reaction time of 4 h. 1H NMR (400 MHz, CDCl3) δ 7.87 (m, 3H), 7.69 (m, 1H), 7.61 (m, 1H), 7.54 (m, 4H), 7.10 (m, 3H), 6.98 (d, 1H), 6.85 (d, 1H), 6.75 (s, 1H), 6.44 (m, 1H), 4.31 (s, 2H), 4.29 (s, 2H), 3.61 (s, 3H), 2.87 (dd, 1H), 2.61-2.47 (m, 2H), 1.06 (d, 3H); MS 504 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6]([CH2:9][NH2:10])([CH3:8])[CH2:5][CH:4]([NH2:11])[CH2:3]1.[CH3:13][CH2:14][CH2:15][C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=O>CO>[CH2:22]([O:21][C:19]([CH:18]=[C:16]([NH:11][CH:4]1[CH2:3][C:2]([CH3:12])([CH3:1])[CH2:7][C:6]([CH:9]([NH:10][C:14]([CH2:15][CH2:16][CH3:18])=[CH2:13])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:8])[CH2:5]1)[CH2:15][CH2:14][CH3:13])=[O:20])[CH3:23]
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Reactant: CCCC(=O)CC(=O)OCC
Solvent: CO
Product: C=C(CCC)NC(C(=O)OCC)C1(C)CC(NC(=CC(=O)OCC)CCC)CC(C)(C)C1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To isophoronediamine (139.23 g, 0.819 mol) in methanol (700 ml) was slowly added with stirring ethyl butyroacetate (262.32 g, 1.660 mol) in methanol (700 ml) over 45 minutes, during which the temperature decreased slightly from 24° C. to 23° C. The reaction mixture was allowed to stand at 22° C. overnight (16 h). Further methanol was added, and removal of solvent and drying (91° C./100 Pa) gave 1-(1-ethoxycarbonyl-2-pent-1-enylamino)-3-(1-ethoxycarbonyl-2-pent-1-enylaminomethyl)-3,5,5-trimethylcyclohexane (EEMTCH formula shown below) as a clear light yellow pourable syrup (356.74 g, 97%), identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)O1.[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([CH2:34][NH:35][C:36]2[N:41]=[C:40](Cl)[N:39]=[C:38]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:37]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>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.C(COC)OC>[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([CH2:34][NH:35][C:36]2[N:41]=[C:40]([C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[N:39]=[C:38]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:37]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)nc(N3CCOCC3)n2)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: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)C1
Temperature: 140 °C
Yield: 53.2 %

Procedure:
To a microwave processing tube was added dimethoxyethane (15 mL), aqueous Na2CO3 (2 molar) (4 mL, 8 mmol, 2 eq), (Ph3P)4Pd (317 mg, 0.55 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.81 g, 8.30 mmol, 1.5 eq) and 3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester (1.3 g, 5.53 mmol) and the vessel was sealed. The mixture was heated to 140° C. for 60 minutes. The solvents were removed and the crude compound was purified by silica gel chromatography using CH2Cl2/Ethyl acetate (10:1) and later CH2Cl2/MeOH/NH3 (15:1:0.1) to give the product as a off-white solid (1.3 g, 53% yield). MS (ESI) m/z=442
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12](O)(=O)CC(O)=O>N1C=CC=CC=1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])(=[O:5])[CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: c1ccncc1
Product: CC(=O)c1ccccc1C(=O)O

Procedure:
Heating at 80° to 85° C. of the phthalic anhydride (5) derived from (1) with malonic acid in pyridine affords the o-acetylbenzoic acid (6). ##STR15##
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15]>C(OCC)(=O)C>[C:1]1([CH:7]2[C:8]3[O:13][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:9]=3[CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCCC1c1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CCC2
Temperature: 130 °C
Reaction time: 2 h
Yield: 19.62 %

Procedure:
A solution of 2-phenylcyclohexanone (1.500 g, 8.61 mmol) and carbonisocyanatidic chloride (0.966 mL, 12 mmol) was stirred at 58° C. in a high-pressure vessel (75 mL) for 1 h. The temperature was raised to 130° C. and the reaction mixture was stirred for 2 h. After cooling to room temperature, the reaction mixture solidified. The solid residue was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuum and the oily residue was purified by column chromatography on silica gel to provide 8-phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.689 mmol, 19.62% yield) as white solid and 4a-phenyl-4-a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (746.4 mg, 3.04 mmol, 35.3% yield) as white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:12]Br>C(O)(=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:12][C:4]1[CH:3]=[N:2][N:1]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH:5]=1
Reactant: BrBr
Reactant: c1cnn(-c2ccncc2)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnn(-c2ccncc2)c1
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)pyridine (Intermediate 7; 1.1 g; 7.5 mmol) in acetic acid (10 mL) was added a solution of bromine (6 mL) in acetic acid (10 mL) dropwise. The reaction mixture was stirred for 4 hours, diluted with saturated aqueous Na2S2O3 (20 mL), and extracted with DCM (10 mL×3). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL), water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 936 mg (55%) of the title compound as a pink solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC1C([O:38][C:39](=O)[CH2:40][CH2:41][CH2:42][O:43][N+:44]([O-:46])=[O:45])=C(F)C(F)=C(F)C=1F>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][O:12][C:39]([CH2:40][CH2:41][CH2:42][O:43][N+:44]([O-:46])=[O:45])=[O:38])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CCCO[N+](=O)[O-])Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(COC(=O)CCCO[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (0.48 g, 1.1 mmol), TEA (0.16 ml, 1.1 mmol) and DMAP (0.14 mg, 1.1 mmol) in DMF (3 ml), cooled to 0° C., a solution of 4-nitrooxybutyric acid pentafluorophenyl ester (0.36 g, 1.1 mmol) in DMF (3 ml) was added. The reaction was slowly warmed to room temperature and stirred for 3 hours. Then the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (10 ml) and washed with a buffer solution (pH=3) then with brine. The organic layer was dried over Na2SO4, concentrated and purified by flash chromatography (CH2Cl2/MeOH 98:2) to afford the title compound (0.41 g, 66%).