Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]#N)[CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH2:14].CC(O)=[O:17].S(=O)(=O)(O)O>CCOCC>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([OH:17])=[O:14])[CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O
Reactant: N#CC1(c2ccc(I)cn2)CCC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=C(O)C1(c2ccc(I)cn2)CCC1
Temperature: 115 °C
Reaction time: 5 h

Procedure:
1-(5-Iodo-pyridin-2-yl)-cyclobutane carbonitrile (4.0 g, 14 mmol) was combined with water (5.0 mL), glacial AcOH (5.0 mL) and concentrated sulfuric acid (5.0 mL). The homogeneous solution was heated to reflux (external bath: 115° C.). After 5 h, the solution was cooled to room temperature and poured into water (10 mL) and Et2O (15 mL). The layers were separated and the Et2O layer was discarded. The aqueous layer was adjusted to pH 4.5-5 by the addition of 2M aq. NaOH and then extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 layers were washed with brine, dried over MgSO4, filtered and concentrated to yield 3.92 g of 1-(5-iodo-pyridin-2-yl)-cyclobutane carboxylic acid, m/z 304.4 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=3[N:13]=[N:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl.CCOCC>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[N:13]=[N:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:3][CH2:4]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)nnc3ccc(Cl)cc32)CC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)nnc5ccc(Cl)cc54)CC3)nc2N1
Yield: 32.3 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one (Intermediate 207, 67 mg) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (360 mg) and sodium acetoxyborohydride (76 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane and trituration from ether gave 33 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=O)[CH:8]=2)[NH:3]1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>CN(C)C=O.C(#N)C>[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH:40][C:11]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2)=[O:13]
Reactant: COc1ccccc1CN
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 2-oxoindoline-5-carboxylic acid (0.200 g, 1.12 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.477 g, 2.47 mmol), diisopropylethylamine (0.586 mL, 3.37 mmol) and catalytic amount of N,N-dimethylaminopyridine in N,N-dimethylformamide/acteonitrile (1:1, 4 mL) was added 2-methoxybenzylamine (0.295 mL, 2.26 mmol) and the reaction mixture stirred at room temperature for 1 h. The solvent was evaporated and the crude material was purified on a short silica gel column using dichloromethane containing 5% methanol as the eluent. This was followed by triturating from ethyl acetate to give 0.10 g (33% yield) of the yellow title compound: 1H NMR (DMSO-d6, 400 MHz) δ 10.60 (br s, 1H), 8.65 (t, J=6 Hz, 1H), 7.79-7.77 (m, 2H), 7.21 (t, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 6.90-6.84 (m, 2H), 4.42 (d, J=6 Hz, 2H), 3.81 (s, 3H), 3.53 (s, 2H); MS (ES) m/z 297 (M++1), m/z 295 (M−−1).
Reaction SMILES: C([N:3]1[C:7]2=[N:8][C:9]3[C:14]([N:15]=[C:6]2[N:5](CC)[CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)C.ClC1N(CC=C)C2=NC3C(N=C2N1CC=C)=CC=CC=3>>[N:5]1[C:6]2=[N:15][C:14]3[C:9]([NH:8][C:7]2=[N:3][CH:4]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: CCN1CN(CC)c2nc3ccccc3nc21
Agent: C=CCN1c2nc3ccccc3nc2N(CC=C)C1Cl
Product: c1ccc2[nH]c3ncnc-3nc2c1

Procedure:
1,3-diethylimidazo[4,5-b]quinoxaline and 6 chloro-1,3-diallylimidazo[4,5-b]quinoxaline;
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][O:17][CH2:18][CH:19]=[CH2:20])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:26](Cl)=[O:27].[C:33]([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:18]([O:17][CH2:16][CH:9]1[C:10]([CH3:33])([O:14][CH3:15])[CH:11]=[CH:12][CH:13]=[C:8]1[C:7]([NH:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:26](=[O:27])[C:25]1[CH:24]=[C:23]([CH3:22])[CH:31]=[C:30]([CH3:32])[CH:29]=1)=[O:21])[CH:19]=[CH2:20]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: O=C([O-])[O-]
Reactant: C=CCOCc1c(OC)cccc1C(=O)NNC(C)(C)C
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C=CCOCC1C(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)=CC=CC1(C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.1 %

Procedure:
To a flask containing 2.0 g (0.0068 mol) of 2-allyloxymethyl-3-methoxy-benzoic acid N′-tert-butyl-hydrazide dissolved in 15 mL of CH2Cl2 was added 1.27 g (0.0075 mol) of 3,5-dimethylbenzoyl chloride in 10 mL of CH2Cl2 and 2.84 g of K2CO3 (0.02 mol) in 30 mL of H2O. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted and partitioned, and the organic phase was dried and solvent was removed in vacuo. The product was purified by silica gel chromatography; eluting in 25% ethyl acetate:hexane fractions, to yield 2.40 g of pure 3,5-dimethyl-benzoic acid N′-(2-allyloxymethyl-3-methyl-3-methoxy-benzoyl)-N-tert-butyl-hydrazide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.2 (t, 1H,) 7.1 (s, 1H), 7.05 (d, 2H), 6.95 (m, 2H), 5.9 (m, 1H), 5.2-5.3 (q, 2H), 4.5 (d, 2H), 3.9 (m, 2H), 3.80 (s, 3H), 2.245 (s, 6H), 1.54 7 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:35]1[N:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1>>[CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:35]3[N:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: Cc1ccc(Cl)nn1
Product: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(C)nn3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 14. Mass spectrum (ESI+): m/z=418 [M+H]+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaB(OAc)3H (6.6 mmol, 1.4 g) was added to a mixture of 4-nitro-benzaldehyde Compound 4a (6.0 mmol, 0.9 g), piperidine Compound 5a (9.0 mmol, 0.9 mL) and glacial acetic acid (5 drops) in CH2Cl2 (50 mL) and the resulting suspension was stirred at r.t. overnight. The reaction mixture was made basic with a 2N NaOH solution and extracted with CH2Cl2. The organic layer was washed with brine, then separated and dried over Na2SO4. The drying agent was filtered and the solvent was removed in vacuo. The product was purified by flash column chromatography (10:1 EtOAc:MeOH) to yield 1-(4-nitro-benzyl)-piperidine Compound 5b as a yellow oil (0.89 g, 67% yield). MS m/e 221 (M+H, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:33])([CH2:31][OH:32])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:19][CH:18]=2)[C:13]1=[O:30])[CH3:11].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(OCC)(=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:33])([CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:21][CH:22]=2)[C:13]1=[O:30])[CH3:11]
Reactant: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (0.5 g) was dissolved in 20 ml of ethyl acetate, to which 0.12 ml of methanesulfonyl chloride and 0.22 ml of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the reaction solution was washed with water (10 ml×2) and 10 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=1:1). The desired fraction was concentrated to give 0.58 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([C:6]1[C:11]([N:12]([CH2:27][O:28][CH3:29])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].[CH3:35][S:36](Cl)(=[O:38])=[O:37].Cl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>N1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:12]([C:11]2[C:6]([C:4](=[O:5])[C:3]3[CH:31]=[CH:32][CH:33]=[CH:34][C:2]=3[NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[N:7][CH:8]=[C:9]([Cl:30])[CH:10]=2)[CH2:27][O:28][CH3:29])(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CS(=O)(=O)Cl
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1N)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: c1ccncc1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1NS(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred suspension of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in pyridine (1 mL) was added methanesulfonyl chloride (26 mg, 0.226 mmol). After 2 h the reaction mixture was poured into 1 M HCl and the aqueous portions were subsequently extracted with EtOAc. The combined extracts were dried and concentrated under reduced pressure. The resulting residue was dissolved in THF (5 mL), treated with TBAF (1 M in THF, 200 L, 0.200 mmol), and then stirred at room temperature for 3-4 h. The reaction mixture was subsequently poured into 1 M HCl and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide 4-chloro-N-[5-chloro-2-(2-methanesulfonylamino-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. MS m/z: 634.0 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)=[O:14])[CH:3]=1.Cl.CN.F[B-](F)(F)F.[N:34]1(OC(N(C)C)=[N+](C)C)[C:38]2C=CC=CC=2N=N1.C(NC(C)C)(C)C>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH:34][CH3:38])=[O:23])=[CH:24][CH:25]=2)=[O:14])[CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOc1nc(C(=O)NCc2ccc(C(=O)O)cc2)cc(N)c1C#N
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(C)NC(C)C
Product: CCOc1nc(C(=O)NCc2ccc(C(=O)NC)cc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.3 %

Procedure:
To a mixture of Example 231A (17 mg, 0.05 mmol) and methylamine hydrochloride (4 mg, 0.06 mmol), was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (24 mg, 0.06 mmol), followed by N,N-diisopropylamine (21 μL, 0.12 mmol). The mixture was stirred at room temperature for 20 h. The crude product was purified via reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) yielding 8 mg (45%) of the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.31 (t, J=7.0 Hz, 3H), 2.77 (d, J=4.3 Hz, 3H), 4.47-4.57 (m, 4H), 7.07 (s, 1H), 7.27-7.42 (m, 4H), 7.78 (d, J=8.2 Hz, 2H), 8.33-8.40 (m, 1H), 9.11 (q, J=6.1 Hz, 1H). MS (ESI+) m/e=354 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19]C)[CH2:15][CH2:14][CH2:13]2)=[O:9])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.ClCCl.C(O)C>ClCCl>[C:25]([C:22]1[CH:21]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:23]=1[OH:24])[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[OH:19])[CH2:15][CH2:14][CH2:13]2)=[O:9])([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1cc2c(cc1C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)c2cc3c(cc2O)CCC3)cc(C(C)(C)C)c1O
Yield: 83.6 %

Procedure:
To a solution of 5-(3,5-di-tert-butyl-4-hydroxybenzoyl)-6-methoxyindan (3.8 g) in dichloromethane (30 ml) was added boron tribromide-dichloromethane (1:2, 3 ml) dropwise with ice-cooling and stirring. The mixture was stirred under ice-cooling for 15 minutes, after which ethanol (5 ml) was added dropwise. The mixture was then washed with water and dried (MgSO4) and the solvent was distilled off. To the residue was added hexane to give crystals of 5-(3,5-di-tert-butyl-4-hydroxybenzoyl)-6-hydroxyindan (3.06 g, 83.6%). Recrystallization from ethanol gave light yellow prisms, m.p. 155°-156° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6]2=[CH:9][C:10]([N+:13]([O-])=O)=[CH:11][CH:12]=[C:5]2[C:4]1=[O:16])[CH3:2]>[Ni].C(O)C>[NH2:13][C:10]1[CH:9]=[C:6]2[C:7](=[O:8])[N:3]([CH2:1][CH3:2])[C:4](=[O:16])[C:5]2=[CH:12][CH:11]=1
Reactant: CCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Ni]
Solvent: CCO
Product: CCN1C(=O)c2ccc(N)cc2C1=O

Procedure:
N-Ethyl-4-nitrophthalimide (28.0 g.) is hydrogenated in 400 ml. of ethanol and in the presence of Raney nickel catalyst (10 g.) at 100° C. and 1500 psi. pressure. The reaction mixture is filtered to remove the catalyst and the filtrate is concentrated to yield the product, 4-amino-N-ethylphthalimide, which is recrystallized from methanol-water mixture. It melts at 169°-171° C.
Reaction SMILES: [O:1]=[C:2]1[C:7](CC2C=CC=CC=2)=[C:6](C)[C:5]2[CH:16]=[CH:17][C:18]([CH:20]=C)=[CH:19][C:4]=2[O:3]1.I([O-])(=O)(=O)=[O:23].[Na+]>O1CCOCC1.O.CC(O)(C)C.[Os](=O)(=O)(=O)=O>[CH:20]([C:18]1[CH:19]=[C:4]2[C:5]([CH:6]=[CH:7][C:2](=[O:1])[O:3]2)=[CH:16][CH:17]=1)=[O:23]
Reactant: C=Cc1ccc2c(C)c(Cc3ccccc3)c(=O)oc2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: O=Cc1ccc2ccc(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 119 %

Procedure:
To the suspension of 2-oxo-3-benzyl-4-methyl-7-vinyl-2H-1-benzopyrane (16.0 g, Example 23) in dioxane (350 mL) and water (75 mL) is added osmium tetraoxide (1.45 mmol) in t-BuOH. The reaction mixture is stirred at room temperature for 30 minutes and sodium periodate (30 g) is added in portions. The solid is filtered out after 30 minutes stirring and the filtrate is partitioned between CH2Cl2 and water. Separation and the organic layer is washed further with H2O and dried over MgSO4. Evaporation of the organic solvent gives the desired 7-formyl coumarin intermediate (12.0 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.Cl[CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[CH:17]1([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15][CH2:14]1
Reactant: C[Si](C)(C)C#CCCCCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1CCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a solution of diisopropylamine (153 g, 1.52 mol) in anhydrous THF (1.0 L) at 0° C., n-butyllithium (2.5 M in hexane, 608 mL, 1.52 mol) was added dropwise. The mixture was stirred for 20 minutes at 0° C. and then cooled to −78° C. To this mixture, a solution of (6-chlorohex-1-yn-1-yl)trimethylsilane (144 g, 0.76 mol) in anhydrous THF (200 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched at room temperature with saturated aqueous NH4Cl (500 mL), and then extracted with pentane (2×200 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent was evaporated on a rotary evaporator. The residue was distilled at 160-162° C./760 Torr to afford the title compound as a colorless liquid (81 g, yield 70%). 1H NMR (CDCl3, 400 MHz): δ 3.05-3.01 (m, 1H), 2.26-2.20 (m, 2H), 2.17-2.10 (m, 2H), 1.93-1.84 (m, 2H), 0.11 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C1COCCN1
Solvent: CC#N
Product: Clc1cncc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
To a solution of 2,6-dichloropyrazine (1.0 equiv.) in acetonitrile (0.3 M) was added morpholine (3.5 equiv.) and the reaction was stirred at room temperature for 20 h. The resulting precipitate was filtered off and the filtrate was concentrated under vacuo. The crude material was partitioned between water and ethyl acetate, the organic phase was dried with sodium sulfate, filtered and concentrated to afford 4-(6-chloropyrazin-2-yl)morpholine in 75% yield. LCMS m/z (M+H)=200.0, Rt=0.61 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH3:18])([CH:15]([CH3:17])[CH3:16])[CH2:12][CH:13]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:13]/[CH2:12][C:11]([CH3:18])([CH3:10])[CH:15]([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)C(C)(C)CC=O
Solvent: ClCCl
Product: CC(C)C(C)(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 80.7 %

Procedure:
Step D In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1 g, 7.7 mmol) was reacted with 3,3,4-trimethyl-pentanal (1.1 g, 8 mmol) in CH2Cl2 at room temperature for 5 h to give [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.5 g, 80%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.2 %

Procedure:
A solution of diisopropylamine (4.86 mL, 34.70 mmol) in dry tetrahydrofuran (212.3 mL) was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (13.88 mL, 34.70 mmol). The resulting reaction mixture was stirred at −78° C. for 15 min and then slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 31.55 mmol) in dry tetrahydrofuran (23.6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (9.43 mL). The resulting bright yellow solution was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (prepared as in Example 1, 7.95 g, 37.86 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7.08 mL) was slowly added. The reaction mixture was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (5.74 g, 58.1%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](OC)=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:26]>CO>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:26])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1c(-c2ccc(Cl)cc2)cnn(Cc2ccccc2)c1=O
Solvent: CO
Product: O=c1c(Cl)c(-c2ccc(Cl)cc2)cnn1Cc1ccccc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of 2-benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one (13.8 g, 42.23 mmol) and POCl3 (20.0 mL) was stirred at 75° C. for 4 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was cooled in an ice bath and water (200 mL) was added. The undissolved material was filtered and washed with water (3×150 mL). To the solid thus obtained was added MeOH (100 mL). The resultant mixture was sonicated for 10 mins, and then was filtered. The collected solid was washed with MeOH (2×50 mL). The solid was then dried in an vacuum oven at 50° C. to give the title compound, 2-benzyl-4-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one, (9.2 g, 66%) as a light brown solid. HPLC: 3.75 min; M+H=331. 1H NMR (CDCl3, 500 MHz): δ 7.73 (1H, s), 7.50 (2H, d, J=10.0 Hz), 7.47 (2H, d, J=10.0 Hz), 7.42 (2H, d, J=10.0 Hz), 7.30-7.38 (3H, m), 5.39 (2H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][NH:8][C:7]=2[CH:16]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]=2[CH:16]=1)#[N:2]
Reactant: COC(=O)C1CNc2cc(C#N)ccc2O1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)N1CC(C(=O)OC)Oc2ccc(C#N)cc21
Temperature: 0 °C

Procedure:
A mixture of methyl 6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (629 mg, 2.88 mmol) and K2CO3 (1195 mg, 8.65 mmol) in dichloromethane (30 mL) was cooled at 0° C. and ethyl chloroformate (0.76 mL, 7.8 mmol) was added. The mixture was heated at reflux temperature for 30 h. The reaction was cooled and extracted with dichloromethane (3×20 mL), dried over Na2SO4 and concentrated. The product 4-ethyl 2-methyl 6-cyano-2H-benzo[b][1,4]oxazine-2,4(3H)-dicarboxylate was obtained as a yellow oil (670 mg, 80% yield) after purification by silica gel column chromatography (0-25% ethyl acetate/hexanes). 1H NMR (400.0 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.53 (dd, J=2.0, 8.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 5.36 (t, J=3.3 Hz, 1H), 4.39 (dd, J=3.5, 14.1 Hz, 1H), 4.27-4.15 (m, 2H), 3.76 (dd, J=3.2, 14.1 Hz, 1H), 3.71-3.67 (m, 3H), 1.25 (t, J=7.1 Hz, 3H).