Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:23][CH3:24])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]([CH3:20])=[C:15]([CH3:21])[C:14]=2[CH:22]=1)(=O)=O.[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(=O)/C=C/C([O-])=O>CO.C(O)C>[CH3:24][O:23][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:22][C:14]2[C:15]([CH3:21])=[C:16]([CH3:20])[C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCOS(C)(=O)=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CO
Solvent: CCO
Product: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 64 %

Procedure:
Method A (45 h at 50° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-3,4-dimethyl-2H-1-benzopyran-2-one (example 75) and 1-phenylpiperazine; yield 64%; fusion point 151°-152° C. (from ethanol and methanol). Fumarate (×0.5 C4H4O4): method E; yield 92%; fusion point 207°-209° C. (from ethanol and methanol).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(#N)C>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1ncccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1ncccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To an acetonitrile solution (5 ml) of 2-methylnicotinic acid (400 mg, 2.92 mmol) and DMF (11.2 μl, 0.156 mmol), oxalyl dichloride (501 μl, 5.83 mmol) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, to obtain a crude product of 2-methylnicotinic acid chloride as a yellow liquid (470 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][N:34]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:33][CH2:32]1
Reactant: O=C(Cl)c1cccs1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 72 (397 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 280 mg (55%) of white solids. M.P. 253° C. 1H NMR (DMSO-d6): δ 3.70 (m, 4H), 3.93 (m, 4H), 5.46 (s, 2H), 7.13–7.17 (m, 3H), 7.27 (m, 2H), 7.44 (d, J=9.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.68 (dd, J=2.6, 9.0 Hz, 1H), 7.79 (d, J=4.0 Hz, 1H), 7.89 (s, 1H). EIMS m/z 508 (M+1). Anal. (C26H20FClN4O2S) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[H-].[Na+].I[CH3:14]>C1COCC1>[Br:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH3:14])[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Brc1ccnc2cn[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc2nccc(Br)c2n1
Temperature: 25 °C

Procedure:
A solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (100 mg, 0.505 mmol) and sodium hydride (24.24 mg, 0.606 mmol) in THF (2.0 mL) was stirred at 0° C. for 15 minutes. Iodomethane (71.7 mg, 0.505 mmol) was added, and the reaction was warmed to room temperature for 1 hour. The reaction was quenched with water, extracted with EtOAc, dried over MgSO4, and evaporated to dryness to give 7-bromo-2-methyl-2H-pyrazolo[4,3-b]pyridine which was used without further purification.
Reaction SMILES: [C:1]([N:4]([C@H:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31](=[O:40])[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@@H:23]([CH3:41])[CH2:22]1)[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2C(OC(C)(C)C)=O)(=[O:3])[CH3:2]>Cl.O1CCOCC1>[NH:9]1[C:10]2[C:6](=[C:5]([N:4]([C@H:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:31](=[O:40])[C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C@@H:23]([CH3:41])[CH2:22]3)[C:1](=[O:3])[CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3cccc4c3ccn4C(=O)OC(C)(C)C)C[C@@H]2C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3cccc4[nH]ccc34)C[C@@H]2C)cc1
Yield: 25.9 %

Procedure:
tert-Butyl 4-{acetyl[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-1H-indole-1-carboxylate (0.035 g, 0.068 mmol) was stirred in 4 N HCl in dioxane (1 mL) for 24 h and then evaporated to dryness. The residue was dissolved in ethyl acetate, washed with 1N NaOH, water, brine, dried over sodium sulphate and evaporated to dryness to give the crude product (0.023 g). The crude was cleaned by silica gel chromatography to give clean N-1H-indol-4-yl-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (0.008 g, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:21])([C:16]([O:18]CC)=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:21])[C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(Br)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(CCc1ccc(Br)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
To a solution of diethyl 2-[2-(4-bromophenyl)ethyl]-2-methylmalonate (55.0 g) of Reference Example 24 in ethanol (300 mL) was added potassium hydroxide (85%, 12.2 g), and the mixture was stirred at 60° C. for 5 hr. The solvent was evaporated under reduced pressure, water was added, and the aqueous layer was washed with ether. The aqueous layer was acidified with hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (50.8 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH2:22]O)([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Li].C1(C)C=CC(S([Cl:55])(=O)=O)=CC=1.[Cl-].[Li+]>CN(C)P(N(C)C)(N(C)C)=O.CCOCC.O>[Cl:55][CH2:22][CH2:21][C:9]12[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=[C:4]1[C:3]1[C:11](=[CH:12][C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([Cl:15])[C:2]=1[Cl:1])[CH2:10]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCO)C2
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]C
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCCl)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of dry nitrogen a solution of {[5,6-dichloro-9a-(2-hydroxyethyl)-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl]oxy}acetic acid (3.71 g, 10 mMole) in hexamethylphosphoramide (25 ml), anhydrous ether (50 ml) and triphenylmethane (10 mg) is stirred at 0° C. Methyllithium (12.6 ml of 1.6M) solution in ether=20 mMole) is added, dropwise with stirring, over a period of 30 minutes. A solution of p-toluenesulfonyl chloride (2 g, 10.5 mMole) in ether (15 ml) is added over a period of 30 minutes. Finally, dry lithium chloride (420 mg; 10 mMole) is added. The mixture is stirred and allowed to warm to room temperature over 20 hours. Ether (25 ml) and water (50 ml) is added and the layers separated. The organic layer is acidified with hydrochloric acid, washed four times with water (50 ml portions) and finally with a brine solution. After drying the organic phase with magnesium sulfate, the solvent is removed by evaporation at reduced pressure and the residue recrystallized from acetonitrile to give the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:43][C:31]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([CH2:30][CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(C)(CCCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CC(C)(CCCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
0.2 g (0.574 mmol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-yl-amide, 0.15 g (0.5 mmol) of methyl 6-bromo-2-methyl-2-phenyl-hexanecarboxylate and 0.083 g (0.6 mmol) of potassium carbonate are dissolved in 10 ml of acetonitrile. The mixture is stirred for 8 hours at 60° C. and for 14 hours at ambient temperature. Then the reaction mixture is poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off in the rotary evaporator. After column chromatography on silica gel (eluant: dichloromethane/methanol=20:1) a highly viscous oil remains.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:16]2[CH:15]=[C:14]([CH3:19])[N:13]=[C:12]([CH3:11])[CH:17]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Cc1cc(O)cc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(Br)cc2C=O)cc(C)n1

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with 2,6-dimethyl-4-hydroxypyridine (2.5 g, 20 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(2,6-dimethyl-pyridin-4-yloxy)-benzaldehyde as an off white solid (Yield 6 g, 98%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:51])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])=[C:24]([C:41]34[CH2:50][CH:45]5[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]5)[CH2:42]3)[CH2:48]4)[CH:23]=2)=[CH:18][CH:17]=1)(C)(C)C>C(Cl)Cl>[C:41]12([C:24]3[CH:23]=[C:22]([C:19]4[CH:18]=[CH:17][C:16](/[CH:15]=[CH:14]/[C:13]([OH:51])=[O:12])=[CH:21][CH:20]=4)[CH:27]=[CH:26][C:25]=3[O:28][CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccc(OCN3C(=O)c4ccccc4C3=O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(-c2ccc(OCN3C(=O)c4ccccc4C3=O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TFA (1.8 ml) was dropped into an ice-cooled solution of (E)-3-[3′-adamantan-1-yl-4′-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethoxy)-biphenyl-4-yl]acrylic acid tert-butyl ester (110 mg, 0.186 mmol) in DCM (1.8 ml), and the mixture was stirred at 0° C. for 10 min. The solvent was removed in vacuo and the residue was rinsed with hexane to obtain, after filtration, 97 mg (98%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH3:28])[CH2:8][C:9](=[O:27])[N:10]([CH3:26])[CH2:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=2)[CH:16]=[CH:15]1)=[O:13])([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl.CCN(C(C)C)C(C)C.O>C(O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:8][C:9](=[O:27])[N:10]([CH2:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=2)[CH:16]=[CH:15]1)=[O:13])[CH3:26])[CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(=O)n1ccc2ccc([N+](=O)[O-])cc21)C(=O)CN(C)C(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(CC(=O)n1ccc2ccc(N)cc21)C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 99.5 %

Procedure:
A mixture of methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester (12.4 g, 30.6 mmol), SnCl2.2H2O (34.5 g, 153.2 mmol) and DIEA (74.8 mL, 429 mmol) in ethanol (112 mL) was heated to 70° C. for 3 h. Water and EtOAc were added and the mixture was filtered through a short plug of Celite. The organic layer was separated, dried over Na2SO4 and concentrated to yield ({[2-(6-Amino-indol-1-yl)-2-oxo-ethyl]-methyl-carbamoyl}-methyl)-methyl-carbamic acid tert-butyl ester (B-26) (11.4 g, quant.). HPLC ret. time 2.11 min, 10-99% CH3CN, 5 min run; ESI-MS 375.3 m/z (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:27])[CH2:5][C:6]1[N:17](S(C2C=CC=CC=2)(=O)=O)[C:9]2=[N:10][CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1.O.C(OCC)(=O)C>C1COCC1>[CH3:3][N:4]([CH3:27])[CH2:5][C:6]1[NH:17][C:9]2=[N:10][CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1
Reactant: CN(C)Cc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 70 °C
Yield: 81.1 %

Procedure:
Sodium hydroxide (1.11 mL, 1.11 mmol, 1M in water) was added to a solution of N,N-dimethyl-1-(5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanamine (0.10 g, 0.28 mmol) in THF (1.5 mL). The reaction mixture was heated at 70° C. for 16 hours. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were then separated. The aqueous layer was extracted once with ethyl acetate. The organic layers were dried over sodium sulfate, filtered, and evaporated to afford N,N-dimethyl-1-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)methanamine (0.05 g, 82%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:42]2[C:41](=[C:43](O)[CH2:44][CH3:45])[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:51]([O:53][CH:54]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH3:52]>C1COCC1.O>[CH:32]1[C:42]2[C:41](=[CH:43][CH2:44][CH2:45][O:67][C:64]3[CH:63]=[CH:62][C:61]([CH2:60][CH:54]([O:53][CH2:51][CH3:52])[C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:66][CH:65]=3)[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CCC(O)=C1c2ccccc2COc2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCC=C2c3ccccc3COc3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0° C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 3-(6H-dibenzo[b,e]oxepin-11-ylidene1-propanol (0.252 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature, and stirring continued for 18 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (4×50 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to an orange gum. This was then purified by column chromatography on silica gel (20% Et2O in petroleum eluent) to give the title compound as an inseparable 4:1 mixture of E and Z double-bond isomers, as a pale yellow gum; 0.252 g (53%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].C[Si](C)(C)CCOCN1C=CN=C1C=O.[CH3:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][O:35][CH2:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH2:42][NH2:43]>>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:43][CH2:42][C:38]2[N:37]([CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:45])([CH3:44])[CH3:31])[CH:41]=[CH:40][N:39]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: C[Si](C)(C)CCOCn1ccnc1CN
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Product: CCOC(OCC)c1ccc(CNCc2nccn2COCC[Si](C)(C)C)cc1

Procedure:
The same procedure as a series of reactions of Example 1, except that 4-(diethoxymethyl)benzaldehyde was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and 1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methaneamine was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain the title compound having the following physical properties.
Reaction SMILES: [CH2:1]([C:7]12[S:14][CH2:13][C:10]([CH2:15][CH2:16][CH3:17])([CH2:11][S:12]1)[CH2:9][S:8]2=[O:18])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].S([O-])([O-])(=O)=[O:20].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[CH2:1]([C:7]12[S:12][CH2:11][C:10]([CH2:15][CH2:16][CH3:17])([CH2:13][S:14]1)[CH2:9][S:8]2(=[O:20])=[O:18])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: O=S(=O)([O-])[O-]
Reactant: C#CCCCCC12SCC(CCC)(CS1)CS2=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: C#CCCCCC12SCC(CCC)(CS1)CS2(=O)=O
Reaction time: 72 h

Procedure:
To a stirred solution of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane-2-oxide (0.302 g.) in dry acetone (120 ml) containing anhydrous magnesium sulphate (0.75 g) at -20° C. was added a solution of potassium permanganate (0.24 g) in dry acetone (25 ml). The mixture was allowed to warm to 20° and stirred for 72 hours. The colourless mixture was filtered through kieselguhr and the solid residue was washed with acetone. The filtrates were evaporated in vacuo and a colourless solid residue was obtained. The residue was purified by chromatography on silica eluting with dichloromethane. 1-(Hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane-2,2-dioxide was obtained as a colourless solid (100 mg).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(#N)C>[N+:9]([C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Solvent: CC#N
Product: Nc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of 1.00 g (6.41 mmol) of 4-fluoro-3-nitroaniline and 3.17 mL (32.1 mmol) of piperidine in 15 mL of acetonitrile under Ar was heated to reflux for 2 h. The mixture was cooled to RT, concentrated in vacuo, dissolved in EtOAc (60 mL) and washed with 1 M NaOH (2×50 mL), water (50 mL), brine (50 mL), and then dried (Na2SO4). Concentration afforded 1.40 g (99%) of the title compound as dark red crystals: 1H-NMR (CDCl3; 400 MHz): δ 7.04 (d, 1H, J=8.6 Hz), 7.03 (d, 1H, J=2.8 Hz), 6.81 (dd, 1H, J=8.6, 2.8 Hz), 2.85-2.88 (m, 4H), 1.65-1.70 (m, 4H), and 1.51-1.55 (m, 2H).
Reaction SMILES: Cl.[C:2]1([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.O[CH2:23][C:24]1[CH:33]=[N:32][C:31]2[N:30]3[CH2:34][CH2:35][CH2:36][C@H:29]3[C:28](=[O:37])[NH:27][C:26]=2[CH:25]=1.CCN(C(C)C)C(C)C>C(#N)CC>[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:23][C:24]3[CH:33]=[N:32][C:31]4[N:30]5[CH2:34][CH2:35][CH2:36][C@H:29]5[C:28](=[O:37])[NH:27][C:26]=4[CH:25]=3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCN(c4ccccc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
1-Phenylpiperazine hydrochloride (11.9 mg, 0.060 mmol), (cyanomethyl)trimethylphosphonium iodide (0.025 g, 0.102 mmoles), and (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (0.014 g, 0.063 mmoles) were diluted with propionitrile (0.5 ml) and treated with DIPEA (0.017 ml, 0.100 mmol). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was washed with water (1 mL) and concentrated. The residue was dissolved in DMSO (1 mL) and purified using HPLC (acetonitrile-water, NH4HCO3 buffered). The fractions were concentrated in vacuo, dissolved in dioxane-water (1:1, 2 mL) and lyophilized to yield the title compound as a white solid (5.1 mg, 23%). [M+H] calc'd for C21H25N5O 364; found, 364.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>OS(O)(=O)=O>[OH:13][C:9]1([C:19]2[CH:20]=[C:21]([O:22][CH3:23])[C:16]([O:15][CH3:14])=[CH:17][C:18]=2[NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: COc1ccc(NC(=O)C(C)C)cc1OC
Agent: O=S(=O)(O)O
Product: COc1cc(NC(=O)C(C)C)c(C2(O)C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
Ninhydrin (1.00 g, 5.6 mmol) was dissolved in conc.H2SO4 (10 ml). This solution was added with N-(3,4-dimethoxyphenyl)isobutyramide (1.25 g, 5.62 mmol) at 0° C. and stirred for 30 min under room temperature. Ice water was added with the reaction mixture, and then washed with ice water and ethylacetate. After drying and filtrating, the ethylacetate layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (1.37 g, 63%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[CH3:24])[NH2:20])([O-:16])=[O:15]>N1C=CC=CC=1>[CH3:24][C:23]1[CH:22]=[CH:21][C:19]([NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[CH:18][C:17]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 3-trifluoromethylbenzoyl chloride (9.9 ml), 3-nitro-4-methylaniline (10 g) and pyridine (100 ml) was stirred and heated to 80° C. for 2 hours. The reaction mixture was evaporated and the residue was triturated under 2N aqueous hydrochloric acid solution. The solid so obtained was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution, water and isohexane and dried under vacuum at 55° C. to give N-(4-methyl-3-nitrophenyl)-3-trifluoromethylbenzamide as a solid (21.9 g); NMR Spectrum: (DMSOd6) 7.49 (d, 1H), 7.78 (m, 1H), 7.99 (m, 2H), 8.27 (m, 2H), 8.51 (s, 1H), 10.77 (s, 1H); Mass Spectrum: M−H− 23.