Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[I-:22].[K+].[Cl-].[NH4+]>CN(C)P(=O)(N(C)C)N(C)C>[I:22][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: [I-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CC1CCc2cc(I)cc3[nH]c(=O)c(=O)n1c23
Temperature: 160 °C
Yield: 77.5 %

Procedure:
A mixture of 9-bromo-5-methoxycarbonylmethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (530 mg, 1.50 mmol), potassium iodide (4.98 g, 30 mmol) and cuprous iodide (2.0 g, 10.5 mmol) in hexamethylphosphoric triamide (5 mL) was heated at 160° C. for 6.5 h and poured into 1N aqueous ammonium chloride (200 mL). The mixture was extracted with a mixed solvent of THF and ethyl acetate (600 mL). The extract was washed with 1N aqueous ammonium chloride (200 mL×2) and brine (200 mL), dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 0.7 to 1% acetic acid/ethyl acetate to give 465 mg of the title compound (78%): mp 241°~243° C.; 1H NMR (270 MHz, DMSO-d6) δ12.01 (bs, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 5.03~5.14 (m, 1H), 3.62 (s, 3H), 2.93 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.78 (dm, 1H, J=17.1 Hz), 2.54~2.69 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.79~1.96 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:25][O:26][C:27](OC)(C)C>C(Cl)Cl>[CH3:25][O:26][CH2:27][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COCOc1ccccc1-c1ccccc1
Yield: 11 %

Procedure:
The procedure as in Example 1: step a was followed using 2-hydroxybiphenyl (1.70 g, 10 mmol), p-toluenesulfonic acid (190 mg, 1.1 mmol), DCM (5 mL), and dimethoxypropane (5 mL). Analogous aqueous workup yielded the title compound (225 mg, 11%) which was used without further purification. 1H-NMR (CDCl3): δ 7.58 (m, 2H), 7.44 (m, 2H), 7.36 (m, 2H), 7.32 (m, 1H), 7.25 (dd, 1H, J=1.2, 8.1 Hz), 7.12 (dt, 1H, J=1.2, 7.4 Hz), 5.14 (s, 2H), 3.42 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[C:35]1[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=1)[C:5]([NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29])[CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[O:6].NN>CO.C1COCC1>[NH2:10][CH2:9][C@@H:8]([NH:7][C:5](=[O:6])[C:4]1[CH:32]=[CH:33][C:34]([C:35]2[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=2)=[C:2]([Br:1])[CH:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Br
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.8 %

Procedure:
To a solution of 3-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)benzamide (172 mg, 0.28 mmol) in MeOH/THF (4 mL, 1:1) at RT was added hydrazine (0.17 mL, 5.5 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound (60.4 mg, 45%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([O:15][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cc1c(C)cc(C(C)(C)C)c(O)c1C

Procedure:
10.68 grams of the compound of Example 5, 11.4 grams of n-octadecanol and 0.8 grams of p-toluene sulfonic acid monohydrate were dispersed in 150 ml of toluene and heated at reflux for seven hours during which the water collected by azeotropic distillation was almost equal to the theory. The reaction mixture was successively washed with water, aqueous saturated sodium bicarbonate solution, and then with water once again until the wash water was neutral. After drying over anhydrous sodium sulfate and filtering free of the drying agent, the clear filtrate was evaporated at reduced pressures to yield the desired product as residue. After successive crystallizations from acetonitrile and n-heptane, the desired compound was isolated as white crystals melting at 57° to 59° C (Compound 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH:12]([C:17]([O:19]C)=[O:18])[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(CCCNC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C(CCCNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To dimethyl malonate (102 mL), a solution of sodium methoxide in methanol (28%, 90.4 mL) was added at room temperature, and the mixture was stirred at 60° C. for 30 minutes. The white suspension was cooled to room temperature. Then, tert-butyl (3-bromopropyl)carbamate (106 g) was added thereto at once, and the mixture was stirred at room temperature for 12 hours. To the reaction solution, water was added, and organic matter was extracted with diethyl ether. The organic layer was washed with a 1 N aqueous sodium hydroxide and saturated sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product of dimethyl {3-[(tert-butoxycarbonyl)amino]propyl}malonate. The obtained ester (94 g) was dissolved in methanol (100 mL). To the solution, a solution of lithium hydroxide monohydrate (13.6 g) in water (300 mL) and methanol (300 mL) was added at 0° C., and the mixture was stirred at room temperature for 15 hours. Methanol was distilled off under reduced pressure, and organic matter was extracted with ethyl acetate. 2 N hydrochloric acid (160 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: methylene chloride-methylene chloride/methanol=10/1) to obtain the title compound (69.1 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[N:8]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3n(CCCCCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Yield: 28.7 %

Procedure:
To a suspension of 5.20 g (30 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 60 ml of DMF was added, while stirring under ice-cooling, 1.44 g (36 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a DMF solution (20 ml) of 9.31 g (30 mmol) of N-(6-bromohexyl)phthalimide. The mixture was stirred for 1.5 hour at 110° C. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to give 3.47 g of the desired compound (28.7%, pale brown solid). NMR(200 MHz,CDCl3) δ: 1.33-1.56(4H,m), 1.68(2H,m), 1.85(2H,m), 2.82(3H,s), 3.67(2H,t,J=7.2 Hz), 4.04(2H,t,J=7.2 Hz), 6.78(1H,d,J=7.4 Hz), 7.47(1H,d,J=8.6 Hz), 7.69(1H,dd,J=8.6,7.4 Hz), 7.67-7.76(2H,m), 7.78-7.88(2H,m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:33]([CH3:35])[CH3:34]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:33]([CH3:35])[CH3:34])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (300 mg, 0.88 mmol), anhydrous Cs2CO3 (573 mg, 1.76 mmol), and KI (30 mg, 0.18 mmol) in DMF (10 mL) is added 2-bromo-propane (330 μL, 3.52 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10-40% EtOAc in heptane) to give a pure product (6) as white solid (174 mg, 52%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.CCCCC>[CH2:33]([O:32][C:30](=[O:31])[N:8]([C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-:22])=[O:21])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:34]
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Reactant: CCOC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-amine (57 gm 170 mmol) was dissolved in tetrahydrofuran (750 mL) and stirred under N2. Cooled in an ice/salt bath to −5° C. To this solution was added drop wise over a period of ˜30 minutes, a solution of potassium t-butoxide (21.2 gm, 189 mmol) in tetrahydrofuran (200 mL), maintaining the temperature between −5° and 0° C. to give a deep red reaction mixture. Stirred at this temperature for 15 minutes before the drop wise addition of a solution of ethyl chloroformate (21.4 gm, 198 mmol) in tetrahydrofuran (100 mL), keeping the temperature below 5° C. The cooling bath was removed and the reaction mixture was allowed to reach ambient temperature over 1 hour to give a light brown hazy solution. Evaporation of the solvent was followed by partition of the residue between saturated brine (50 mL) and t-butyl methyl ether (300 mL). The organic phase was washed with water (50 mL) followed by saturated brine (50 mL), dried over sodium sulphate, filtered and evaporated to give a brown oil. The oil was dissolved in n-pentane (250 mL) and stored at ambient temperature overnight. The n-pentane solution was decanted from a dark brown tar which had precipitated out. Evaporation of the solvent gave ethyl-[2-chloro-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate as a pale brown viscous oil (63 gm, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[C:5]#[N:6].[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6]
Reactant: COc1cc(Cl)cc(C#N)c1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: N#Cc1cc(O)cc(Cl)c1
Temperature: 175 °C
Yield: 91 %

Procedure:
A 250 mL round bottom flask was charged 3-chloro-5-methoxybenzonitrile (4.2 g; 25.05 mmol) and 2,4,6-collidine (60 mL) was added. The mixture was stirred under an argon atmosphere until the solution was homogeneous. Anhydrous lithium iodide (10.06 g; 75.18 mmol) was added and the mixture was heated to 175° C. for 3 h. The reaction mixture was cooled to RT and partitioned between 10% HCl and EtOAc. The EtOAc phase was washed sequentially with 10% HCl and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford a oil which was crystallized from hexanes to afford 3-chloro-5-hydroxybenzonitrile (130c, 3.5 g, 91% theory).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15]C(=O)C)[C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([OH:15])[C:5]=2[CH:6]=1
Reactant: COC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(O)c2cc(C)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methyl-4-acetoxy-6-methoxycarbonylbenzofuran (Method 14; 1.275 g, 5.14 mmol) was added to a suspension of potassium carbonate (1.408 g, 10.3 mmol, 2 eq) in MeOH (100 ml) and water (2 ml), and the mixture stirred for 1 hr at ambient temperature. The supernatant liquor was decanted from the insoluble material and evaporated in vacuo to yield a cream solid (2.19 g, assumed to be contaminated with inorganics). NMR: 2.35 (s, 3H), 3.56 (br s, 1H), 3.73 (s, 3H), 6.46 (s, 1H), 6.69 (s, 1H), 6.86 (s, 1H); m/z 205 (M−H)−, 83% by LC-MS.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10])=C1.[O:12]1C=CC=[C:13]1C=O>O1CCCC1>[O:12]1[CH:13]=[CH:5][CH:4]=[C:3]1[CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10]
Reactant: OCCCC(O)c1ccsc1
Reactant: O=Cc1ccco1
Solvent: C1CCOC1
Product: OCCCC(O)c1ccco1

Procedure:
The Grignard reagent prepared in Example 26 step (a) (0.7 M, 28 ml, 19.6 mmol), and furan-2-carboxaldehyde (1.92 g, 20 mmol) in anhydrous tetrahydrofuran (15 ml) were used to prepare the sub-title compound, using the procedure described in Example 26 step (a). The product was a colourless oil (2.69 g, 88%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(#N)C>[CH2:12]([N:14]([CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CCNCC
Reactant: O=Cc1cc(CCl)ccc1O
Solvent: CC#N
Product: CCN(CC)Cc1ccc(O)c(C=O)c1
Yield: 150.8 %

Procedure:
To a solution of 5-(chloromethyl)salicylaldehyde (14)(345 mg, 2 mmol) in acetonitrile (70 mL), diethylamine (0.21 mL, 2 mmol) was added and the mixture refluxed overnight. Then, the solvent was evaporated to give compound 15 (625 mg, 99%) as a yellow oil. □max 3383, 2648 and 1653 cm−1. 1H-NMR δH 1.37 (6H, t, J=7.2 Hz, 2×CH2CH3), 3.43 (4H, q, J=7.2 Hz, 2×CH2CH3), 4.09 (2H, s, CCH2N), 7.05 (1H, d, J=8.6 Hz, HAr), 8.03 (1H, d, J=8.6 Hz, HAr), 8.14 (1H, s, HAr), 9.98 (1H, s, CHO), 12.32 (1H, br s, OH). 13C-NMR δC 11.4, 46.4, 56.0, 118.8, 121.3, 136.7, 139.0, 162.7, 196.5. m/z(ESI) 208 (MH+, 100), 293 (30), 317 (10). HRMS (ESI): Calculated for M+ (C12H17NO2+) 208.1338. Found 208.1355.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CN(C)C(=O)C>[C:23]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH2:1])=[O:22])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 30 mg, 0.10 mmol) was stirred and dissolved in N,N-dimethylacetamide (2 ml) and acetic anhydride (0.011 ml, 0.11 mmol) added. The reaction was stirred at ambient temperature for 1 hour and then partitioned between water and ethyl acetate. The organic layer was separated, washed with brine and dried over magnesium sulfate, filtered and evaporated to give the title compound as a colourless solid (23 mg, 68%); NMR Spectrum: (DMSO-d6) 1.48 (m, 1H), 1.64 (m, 1H), 1.79 (m, 2H), 2.02 (s, 3H), 2.59 (m, 1H), 2.84 (m, 1H), 3.13 (m, 1H), 3.92 (d, 1H), 4.53 (d, 1H), 4.85 (s, 2H), 6.58 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.15 (d, 1H), 7.37 (d, 2H), 7.90 (d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H+ 338.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH3:34]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][C:25]([NH2:34])=[O:27])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCn1c(=O)c(CCCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1c(=O)c(CCCC(N)=O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C

Procedure:
To a THF solution of 4-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]butanoic acid were added oxalyl chloride and one drop of DMF, followed by stirring at room temperature. The reaction mixture was added dropwise to an ice-cooled THF solution of concentrated aqueous ammonia and then, the whole was stirred for 30 minutes. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 4-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]butanamide. To a dichloroethane solution of the resulting compound were added pyridine, phosphorus oxychloride and one drop of DMF, followed by stirring at room temperature. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 4-(3-chlorophenyl)-3-(3-cyanopropyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one. NMR1: 6.90 (1H, d, J=8.2 Hz), 4.67 (2H, q, J=7.1 Hz), 1.70-2.10 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:17])=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([Cl:17])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Yield: 91 %

Procedure:
A mixture of 50 g. of 3-(3-nitrophenyl)propenoic acid, 24.54 ml. of thionyl chloride and 300 ml. of benzene were heated under reflux for 2.5 hours. The cooled solution was filtered and then it was evaporated in vacuo. The residue was recrystallized from carbon tetrachloride, to give 49.9 g. (91% yield) of the title compound, m.p. 81°-83.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:12][CH3:13])([O:9][CH2:10][CH3:11])[C:7]([O:14][CH3:15])=[CH:6][C:5](OCC)([CH3:16])[CH:4]=1.Cl(O)(=O)(=O)=O>C(Cl)Cl>[CH3:15][O:14][C:7]1[C:8]([O:12][CH3:13])([O:9][CH2:10][CH3:11])[C:3]([O:2][CH3:1])=[CH:4][C:5](=[CH2:16])[CH:6]=1
Reactant: CCOC1(C)C=C(OC)C(OC)(OCC)C(OC)=C1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: C=C1C=C(OC)C(OC)(OCC)C(OC)=C1
Yield: 97.4 %

Procedure:
The same procedure as in Example 9 was repeated using 272 mg of 1,5,6-trimethoxy-3,6-diethoxy-3-methyl-1,4-cyclohexadiene, 10 mg of methylene chloride and 10 mg of perchloric acid recovering 230 mg of an oily crude product. The crude product was purified by silica gel column chromatograph using a 20:1 benzeneethyl acetate mixture giving 220 mg of 1,5,6-trimethoxy-6-ethoxy-3-methylidene-1,4-cyclohexadiene in 92% of theoretical yield. The compound thus obtained was identified by NMR.
Reaction SMILES: [CH2:1](NCC)C.[SH:6][CH:7]([CH3:16])[CH:8]([S:10][CH:11](C)[CH:12]([OH:14])[CH3:13])[CH3:9]>CO>[SH:6][CH:7]([CH3:16])[CH:8]([S:10][CH2:11][CH:12]([OH:14])[CH2:13][CH3:1])[CH3:9]
Reactant: CCNCC
Reactant: CC(O)C(C)SC(C)C(C)S
Solvent: CO
Product: CCC(O)CSC(C)C(C)S
Reaction time: 8 h

Procedure:
To a refluxing mixture of methanol (30 cc) and diethyl amine (15 cc) at 59°C is added 0.8 grams of threo-3-mercapto-2-butanol produced according to Example II and 0.3 grams of cis-2,3-butane episulfide produced according to Example III (0.3 grams). The reaction mass is refluxed for a period of 5 hours at 59°-64°C, after which time it is allowed to remain at room temperature overnight. The reaction mass is then reheated to 61°C and allowed to remain at that temperature for a period of 3 hours after which GLC analysis indicated that most of the starting material is reacted. The major product is isolated via GLC (same conditions as Example VII) and analyzed via mass spectral, NMR and IR analyses to be the threo-threo 3((2-mercapto-1-methylpropyl) thio)-2-butanol having the structure: ##SPC23##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH2:13]([O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16]([C:18]1([NH:27][C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3cc[nH]c23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 1H-indole-7-carboxylic acid (250 mg, 1.55 mmol), 2-Amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-60% EtOAc in heptane) to give a pure product (57) as white solid (378 mg, 70%).