Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:35][NH:36][C:37](=O)[CH2:38][O:39][CH3:40])=[N:10][N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:37]([CH2:38][O:39][CH3:40])=[N:36][N:35]=3)[N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: COCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccc(C#N)cc2)c1-c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(C#N)cc3)c(=O)n(Cc3ccc(C(F)(F)F)nc3C)n12
Temperature: 120 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl) -2-methoxyacetohydrazide (780 mg, 1.338 mmol) was dissolved in toluene (25 ml) and was heated at 120° C. for 15 min. After this time, POCl3(5 ml) was added and the reaction was stirred at 120° C. for an additional 2 hr. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (50 ml) and washed with saturated NaHCO3(20 ml), water (20 ml) and saturated NaCl (20 ml). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified using an ISCO automated system (80 g silica gel, 20%-80% EtOAc/Hex) to give the product 4-(8-(4-chlorophenyl)-3-(methoxymethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (550 mg) as an off-white solid (73% yield). HPLC retention time 3.085 min (Method A); LCMS (M+H)=565.0. 1HNMR (CD3CN, 500 Hz) 7.67(1H, d, J=7.7Hz), 7.63(2H, d, J=8.8 Hz), 7.58(1H, d, J=7.75), 7.35-7.37(6H, m), 5.81(2H, s), 4.40(2H, s), 3.24(3H, s), 2.65(3H, s); 13CNMR (CD3CN, 500 Hz) 160.24, 157.25, 146.50(m), 146.00, 144.71, 139.15, 137.77, 135.93, 134.84, 134.25, 132.92, 132.64, 131.38, 129.26, 122.90(m), 119.25, 112.66, 65.06, 58.28, 50.01, 22.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:28]([F:31])([F:30])[F:29])=[C:24]([CH:27]=1)[CH:25]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:28]([F:29])([F:30])[F:31])=[C:24]([CH:27]=1)/[CH:25]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Cl)ccc1C(F)(F)F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0404 mmol) in toluene 5 mL was added 5-chloro-2-(trifluoromethyl)benzaldehyde 51 (84.4 mg, 0.404 mmol) and PTSA (153.9 mg, 0.809 mmol). The reaction was stirred at 120° C. for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 52. The crude 52 was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(5-chloro-2-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 52 was eluted at 28% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:27][C@H:28]2[O:30][CH2:29]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[O:30]1[CH2:29][C@H:28]1[CH2:27][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(OC[C@@H]3CO3)cccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
1-Naphthol (1.0 g) was dissolved in DMF (8 ml) under nitrogen atmosphere and the solution was cooled to 0° C. 25 Cesium fluoride (2.1 g) was added thereto and the mixture was stirred for 1 hour. Then, (S)-glycidyl m-nitrobenzenesulfonate (1.80 g, 99.3% e.e.) was added thereto and the mixture was stirred for 24 hours at the same temperature. After the reaction water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/ethyl acetate; 6:1) to give 1.34 g of (S)-1-(2,3-epoxypropoxy)naphthalene (yield 96.5%, optical purity 99.2% e.e.) as a colorless oil.
Reaction SMILES: II.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][CH2:37][C:38]([NH:40][NH:41][C:42](=[O:44])[CH3:43])=O)([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][CH2:37][C:38]1[O:44][C:42]([CH3:43])=[N:41][N:40]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)NNC(=O)CCNC(=O)OC(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nnc(CCNC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Iodine (0.261 g, 1.028 mmol) is added to a stirred solution of polymer supported triphenylphosphine (3 mmol/g, 0.34 g, 1.03 mmol) in DCM (10 ml). After stirring for 10 min at room temperature triethylamine (0.287 ml, 2.06 mmol) and [3-(N′-acetyl-hydrazino)-3-oxo-propyl]-carbamic acid tert-butyl ester (0.126 g, 0.514 mmol) are added. The reaction is stirred at room temperature for 18 h then filtered through a Celite™ filter material plug, washing with DCM. The solvent is removed and the residue is purified by chromatography on silica, eluting with EtOAc, to afford the titled compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>CCOC(C)=O.O>[CH2:18]([O:17][C:15]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
To a suspension of piperazine-2-one (2.00 g, 20.0 mmol) in EtOAc (50 mL) and water (50 mL), were added sodium carbonate (6.36 g, 60.0 mmol) and 95% benzyl chloroformate (3.59 mL, 24.0 mmol) and the mixture was stirred for 3 days at rt. To the mixture were added EtOAc (50 mL) and water (20 mL) and then organic layer was separated. The aqueous layer was extracted with EtOAc (30 mL×2). The combined organic layer was washed with brine (20 mL) and then dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with diethyl ether (50 mL) to give title compound (3.98 g, 85%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:15])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CC(=O)CC.O>[CH3:15][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:10][CH:9]=2)[N:6]=1
Reactant: Cc1cc(CO)n(-c2ccc(O)cc2)n1
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1cc(CO)n(-c2ccc(OCCCN3CCCC3)cc2)n1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a solution of 4-(5-hydroxymethyl-3-methylpyrazol-1-yl)phenol (326 mg, 1.60 mmol) in 2-butanone (8 mL) was added potassium carbonate (243 mg, 1.76 mmol) and 1-(3-chloropropyl)pyrrolidine (260 mg, 1.76 mmol). The reaction was heated overnight at 80° C. After the reaction was diluted with water and extracted with methylene chloride, the organic layer was dried (MgSO4) and concentrated to give 315 mg of the desired product. LC-MS (C18H25N3O2 calculated 315) m/z 316 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([NH:14][N:5]2[C:6](=[O:13])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([CH2:2][NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:4]2)=[O:24])=[CH:22][CH:21]=1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 42 and pivaloyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.45 (d, J=7.8 Hz, 1H), 8.23-8.26 (bs, 1H), 7.73-7.96 (m, 3H), 7.29-7.51 (m, 4H), 6.45-6.47 (m, 1H), 4.74-4.77 (m, 2H), 3.80-3.82 (m, 2H), 1.21 (s, 9H); MS (ESI−) M/Z 425 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1.FC(F)(F)C(O)=O>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.53 g, 4.77 mmol) in DMF (20 mL) was added NIS (1.18 g, 5.24 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 5 h at ambient temperature, the reaction was quenched by saturated NH4Cl (aq.). The solution was extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL) successively, dried over Na2SO4 and concentrated in vacuo to give the desired product (yellow solid, 1.90 g, 89.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.73 (s, 1H), 8.58 (d, 1H), 7.47 (m, 1H), 7.39 (m, 1H), 6.74 (m, 1H), 4.03 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][O:40]C1CCCCO1.Cl>CN(C=O)C.CO>[F:28][C:26]([F:29])([F:27])[CH2:25][N:21]1[C:20]([C:14]2[CH:15]=[C:16]3[N:12]([C:11]4[CH:30]=[C:7]([CH:4]5[CH2:3][CH2:2][N:1]([CH2:38][CH2:39][OH:40])[CH2:6][CH2:5]5)[CH:8]=[CH:9][C:10]=4[O:19][CH2:18][CH2:17]3)[N:13]=2)=[N:24][CH:23]=[N:22]1
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Reactant: BrCCOC1CCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: OCCN1CCC(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A mixture of 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (180 mg, 0.43 mmol) in DMF (1 mL), potassium carbonate (89 mg, 0.65 mmol) and 2-(2-bromo-ethoxy)-tetrahydro-pyran (97 L, 0.65 mmol) was heated at 50° C. for 18 h. The cooled reaction mixture was partitioned between ethyl acetate and water, the aqueous layer extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH (+2M NH3) in DCM) to give a colourless oil. The oil was dissolved in methanol and treated with 1M HCl in methanol (2 mL, 2 mmol) and the reaction mixture stirred for 2 h at RT before concentrating in vacuo. The resultant residue was triturated in a mixture of diethyl ether and methanol to give 142 as a pale yellow solid (115 mg, 54%). 1H NMR (DMSO-d6, 400 MHz): δ 9.81 (br s, 1H); 8.22 (s, 1H); 7.70 (s, 1H); 7.32-7.24 (m, 2H); 6.99 (s, 1H); 5.72 (q, J=8.7 Hz, 2H); 5.36 (br s, 1H); 4.51 (t, J=6.0 Hz, 2H); 3.80 (t, J=4.9 Hz, 2H); 3.67-3.57 (m, 2H); 3.22-3.06 (m, 6H); 2.97-2.85 (m, 1H); 2.10-2.00 (m, 4H). LCMS: RT=6.62 min, M+H+=463.1
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][CH:9]([CH3:26])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](ON1C(=O)CCC1=O)=[O:17])=[O:11]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH:9]([CH3:8])[CH3:26])=[O:17])[C:5]([OH:7])=[O:6]
Reactant: N[C@H](CO)C(=O)O
Reactant: CC(C)C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: CC(C)C(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 40.3 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylpropanoate (546 mg, 2.0 mmol) were reacted to provide 212 mg (40% yield) of the title compound (29) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.79 (m, 1H), 6.03 (t, 0.2H), 5.58 (br s, 1H), 4.41 (m, 1H), 4.05 (m, 1H), 3.94 (m, 1H), 2.57 (m, 1H), 1.48 (2d, 3H), 1.19 (2d, 6H). MS (ESI) nm/z 281.11 (M+NH4)+; 286.11 (M+Na)+; 262.12 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC(C(=O)CC2C=CN=CC=2)=C([F:50])C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[C:13]([F:50])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1F
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2F)n1

Procedure:
Following the procedure for the preparation of 4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol4-yl]-pyridine but substituting 1-(4-Benzyloxy-2-fluoro-phenyl)-2-pyridin4-yl-ethanone provided the title compound. MS: (M+H m/z=360.1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Br[CH2:32][CH2:33][OH:34].C([O-])(O)=O.[Na+]>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:32][CH2:33][OH:34])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 70.2 %

Procedure:
To a solution of COMPOUND 249 (0.1189 g, 0.38 mmol) in CH3CN (4 mL) was added Et3N (0.08 mL, 0.57 mmol), KI (0.0063 g, 0.04 mmol), and 2-bromoethanol (0.03 mL, 0.46 mmol), and stirred at room temperature for 23 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (25:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0946 g (66%) of COMPOUND 339 as a pale yellow oil. 1H NMR (CDCl3) δ 1.71-1.98 (m, 6H), 2.09 (s, 6H), 2.46 (t, 3H, J=5.1 Hz), 2.94 (d, 3H, J=10.8 Hz), 3.56 (t, 2H, J=5.1 Hz), 3.82 (s, 4H), 7.04-7.08 (m, 2H), 7.34 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 18.35, 27.34, 53.93, 55.13, 57.82, 58.52, 59.74, 122.63, 133.76, 138.29, 146.15, 157.80. ES-MS m/z 355.5 (M+H). Anal. Calcd. for C21H30N4O.0.3CH2Cl2: C, 67.33; H, 8.12; N, 14.74. Found: C, 67.46; H, 8.43; N, 14.93.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([CH3:13])([CH2:11][CH3:12])[C:3]1=[CH2:14].[N:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[OH:27])=O>C(O)C>[CH3:1][N:2]1[C:10]2=[N:9][CH:8]=[CH:7][CH:6]=[C:5]2[C:4]([CH3:13])([CH2:11][CH3:12])[C:3]21[CH:14]=[N:15][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27]2
Reactant: COc1cc(O)c(N=O)c(OC)c1
Reactant: C=C1N(C)c2ncccc2C1(C)CC
Solvent: CCO
Product: CCC1(C)c2cccnc2N(C)C12C=Nc1c(OC)cc(OC)cc1O2

Procedure:
5.0 grams of the thus prepared 1,3-dimethyl-3-ethyl-2-methylene-1,7-diazaindane product were added to about 80 milliliters of ethanol and warmed in a 100 milliliter round bottom flask. When the internal temperature of the flask contents reached 60° C., 3.3 grams of 2-nitroso-3,5-dimethoxyphenol were added to the flask. The mixture was allowed to reflux overnight. The reaction mixture was allowed to cool down and a silica gel column was used to isolate the desired product, i.e., 1',3'-Dihydro-1',3'-dimethyl-3'-ethyl- 5,7-dimethoxyspiro-[2H-1,4-benzoxazine-2,2'-[2H]pyrrolo[2,3-b]pyridine]. Identification was confirmed by appropriate spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:15][O:16][C:17](=[O:24])[CH2:18]/[C:19](/[C:20]([O:22][CH3:23])=[O:21])=[CH:6]\[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(=O)CCC(=O)OC
Product: COC(=O)C/C(=C\c1cc(OC)c(OC)c(OC)c1)C(=O)OC

Procedure:
3,4,5-Trimethoxybenzaldehyde and succinic acid dimethyl ester are treated in the same manner as in Reference Example 1 to give (E)-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-3-butenoic acid methyl ester as pale yellow syrup.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2cccc3ccccc23)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2cccc3ccccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 0.167 gm (0.88 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.200 gm (0.88 mmol) 4-hydroxy-4-(naphth-1-yl)piperidine in 10 mL methanol was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and was then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted again with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 5% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 0.309 (84%) of the title compound as an off-white solid.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[C:22]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:38]3[C:33](=[C:34](O)[CH:35]=[CH:36][C:37]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:32][CH2:31][C:30]2=[O:46])=[CH:24][CH:23]=1>ClCCl>[C:22]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:38]3[C:33](=[C:34]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[CH:35]=[CH:36][C:37]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:32][CH2:31][C:30]2=[O:46])=[CH:24][CH:23]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCc2c(O)ccc(-c3ccccc3)c2N1Cc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CCc2c(OS(=O)(=O)C(F)(F)F)ccc(-c3ccccc3)c2N1Cc1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
Pyridine (1.12 ml) and trifluoromethanesulfonic anhydride (1.99 ml) were added with stirring at 0° C. to an anhydrous dichloromethane solution (40 ml) of 1-(biphenyl-4-ylmethyl)-5-hydroxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one (4.0 g), followed by stirring for 1 hour. The resulting mixture was concentrated under reduced pressure, water was added to the residue, and extraction with dichloromethane was performed. The extract was washed with water, an aqueous potassium hydrogensulfate solution and water in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 5.45 g (yield: quantitative) of 1-(biphenyl-4-ylmethyl)-8-phenyl-5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one as a white amorphous solid.
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=3)[CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1>>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:39]([C:36]4[CH:37]=[C:38]5[C:33]([CH:32]=[CH:31][N:30]=[C:29]5[NH:28][CH2:27][C:26]5[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:43][CH:42]=5)=[CH:34][CH:35]=4)=[O:40])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1ccc(CNc2nccc3ccc(C(=O)O)cc23)cc1
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: Cl
Product: COc1ccc(CNc2nccc3ccc(C(=O)N4CCC5(CC4)Cc4cn(C(C)(C)C)nc4C(=O)N5)cc23)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Example 3, using 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4) and 1-(4-methoxybenzylamino)isoquinoline-7-carboxylic acid (Intermediate 27). +ESI (M+H) 553.5.
Reaction SMILES: [C:1]([CH:8]1[CH2:13][C:12]2([CH2:16][NH2:17])[CH2:14][CH2:15][C:9]1([C:18]([OH:20])=O)[CH2:10][CH2:11]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)([N:23]1C=CN=C1)=O.[NH4+].[OH-].O>CN(C=O)C>[C:1]([CH:8]1[CH2:13][C:12]2([CH2:16][NH2:17])[CH2:11][CH2:10][C:9]1([C:18]([NH2:23])=[O:20])[CH2:15][CH2:14]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C1CC2(CN)CCC1(C(=O)O)CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CC2(CN)CCC1(C(N)=O)CC2

Procedure:
A stirred solution under N2 of 12.0 g (42.5 mmol) of the product from step B in 100 ml of DMF was treated with 8.0 g (49.3 mmol) of carbonyldiimidazole. After 30 min the DMF was evaporated in vacuo to afford 50-60 ml of a light brown paste, which was stirred and treated with 70 ml of conc. NH4OH rapidly added. The initial solution turned to a white paste within 30 min, after which H2O was added up to a total volume of 400 ml to complete precipitation of product, which was triturated and isolated by filtration and washing with H2O, and dried in vacuo to yield the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1Cl)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[CH3:15][O-:16].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:16][CH3:15])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1

Procedure:
Methyl 3-nitro-4-chlorobenzoate (COMPOUND XIII) (see above for synthesis of 4-chloro-anti-CG) (1 equivalent) is treated with sodium methoxide (1.1 equivalent) in methanol with heating to produce the methyl 3-nitro-4-methoxybenzoate (COMPOUND XIV) which is purified by column chromatography and/or crystallization.