Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[CH:4][C:5]#[N:6].[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].Cl>C(O)C.O.C(OCC)(=O)C>[C:5]([CH:4]=[C:3]([NH:2][C:15](=[O:19])[O:16][CH2:17][CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])#[N:6]
Reactant: N#CC=C(N)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl

Procedure:
4.85 g (211 mmol) of sodium are dissolved in ethanol (260 ml), 30.0 g (141 mmol) of 3-amino-3-(2,4-dichlorophenyl)acrylonitrile and 36.59 g (310 mmol) of diethyl carbonate are added, and the reaction solution is stirred under reflux for 4 h. Ethyl acetate and water are added to the reaction mixture, and the pH is adjusted to pH=5 with concentrated hydrochloric acid. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 7:1 to 1:1); the product has Rf=0.5 in cyclohexane/ethyl acetate 1:1. 17.1 g (43% of theory) of the product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:27])[CH2:9][CH2:10][CH2:11][N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17](C(OC)=O)[CH:18]=2)[C:13]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[N-]=[N+]=[N-].P([O-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(O)C1C=CC=CC=1.C(OC(N(C)CCCN1CCC2C(=CC=[C:82]([NH:87][C:88](=[O:97])[O:89][CH2:90][C:91]3[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=3)C=2)C1=O)=O)(C)(C)C.CI.[H-].[Na+]>O1CCCC1.CO.CN(C)C=O.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]([CH3:27])[CH2:9][CH2:10][CH2:11][N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:82][NH:87][C:88](=[O:97])[O:89][CH2:90][C:91]3[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=3)[CH:18]=2)[C:13]1=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)CCN(CCCN(C)C(=O)OC(C)(C)C)C2=O
Reactant: CN(CCCN1CCc2cc(NC(=O)OCc3ccccc3)ccc2C1=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Solvent: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCCN1CCc2cc(CNC(=O)OCc3ccccc3)ccc2C1=O)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
The compound (535 mg, 1.41 mmol) obtained in Example 61c was dissolved in a mixed solvent (6 mL) of tetrahydrofuran and methanol (1:1), a 1 N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 60° C. for 5 hours. After the reaction was completed, a 1 N aqueous hydrochloric acid solution (10 mL) was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in 1,4-dioxane (6 mL), diphenyl phosphate azide (0.238 mL, 1.10 mmol), triethylamine (0.154 mL, 1.10 mmol) and benzyl alcohol (0.228 mL, 2.21 mmol) were added under ice cooling, and the mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the resulting crude benzyl (2-{3-([tert-butoxycarbonyl)(methyl)amino]propyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamate (354 mg, 0.757 mmol) was dissolved in N,N-dimethylformamide (7 mL), methyl iodide (0.236 mL, 3.79 mmol) and 55% sodium hydride (40 mg, 0.909 mmol) were added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, water was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:5, v/v) to give the title compound (320 mg; yield, 88%) as a colorless oily substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:21])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:21][N:7]1[C:6]([CH2:4][OH:3])=[CH:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)=[N:8]1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CO

Procedure:
In analogy to the procedure described for example 1 a], 2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol as white crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CCc1ccccc1
Reaction time: 5 h
Yield: 91.6 %

Procedure:
To a solution of (S)-(+)-N-Boc-2-styrylpyrrolidine (0.56 g, 2.1 mmol) in 10 mL of methanol was added a catalytic amount of 10% Pd/C. The mixture was hydrogenated on a Parr shaker at 50 psi for 5 h. The mixture was filtered and the solution was concentrated under reduced pressure to give the title compound as a light yellow oil (0.53 g, 95%). ES (+) MS m/e=276 (M+H).
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:17].C(OCC)(=O)C>>[ClH:17].[OH:15][CH:10]([CH2:9][NH:8][CH3:6])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(O)CN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCC(O)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of methyl 3-[(tert-butoxycarbonyl)(methyl)amino]-2-hydroxypropanoate (0.2 g) and 4N hydrochloric acid-ethyl acetate (5 mL) was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, to give the title compound (0.1 g, 100%) as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1(O)[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:24][CH2:23][C:18]2([O:19][CH2:20][CH2:21][O:22]2)[CH2:17][CH:16]=1
Reactant: COCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(OCOC)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCOc1ccc(C2=CCC3(CC2)OCCO3)c(OCOC)c1
Yield: 70.7 %

Procedure:
8-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol (1.40 g) was placed in a round bottomed flask fitted with Dean-Stark apparatus. Toluene (30 ml) was added, followed by camphor sulphonic acid (10 mg). The stirred solution was then heated under reflux for 1 hr, cooled, and saturated aqueous sodium bicarbonate solution (10 ml) added. The mixture was poured into a separating funnel and the phases separated. The aqueous phase was extracted with ethyl acetate (2×15 ml) and the combined organics were washed with brine (15 ml), dried over anhydrous magnesium sulphate, filtered and then concentrated in vacuo yielding an orange oil, which was purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 45:55, v/v) to afford the title product (0.94 g) as a colourless oil. δH (CDCl3) 1.84 (2H, t), 2.41-2.43 (2H, m), 2.56-2.62 (2H, m), 3.47 (6H, s), 3.98-4.02 (4H, m), 5.13 (4H, s), 5.58-5.63 (1H, m), 6.64 (1H, dd), 6.78 (1H, d), 7.08 (1H, d).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:30][CH2:31][CH3:32])=[C:15]([C:17]2[NH:18][C:19](=[O:29])[C:20]3[CH:25]=[N:24][N:23]([CH2:26][CH2:27][CH3:28])[C:21]=3[N:22]=2)[CH:16]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:31]([O:30][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:16][C:15]=1[C:17]1[NH:18][C:19](=[O:29])[C:20]2[CH:25]=[N:24][N:23]([CH2:26][CH2:27][CH3:28])[C:21]=2[N:22]=1)[CH3:32]
Reactant: CCCn1ncc2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nc21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1ncc2c(=O)[nH]c(-c3cc(C(=O)CN4CCOCC4)ccc3OCC)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
Morpholine (0.175 g, 0.002 mol) was added to a stirred suspension of 6-(5-bromoacetyl-2-ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Preparation 4; 0.70 g, 0.0017 mol) and anhydrous potassium carbonate (0.461 g, 0.0033 mol) in acetonitrile (30 ml) and the resulting mixture stirred at room temperature for 3 hours. The solvent was removed by evaporation under vacuum, the residue partitioned between water (20 ml) and dichloromethane (30 ml), the organic phase removed and the aqueous phase extracted with dichloromethane (3×30 ml). The combined organic solutions were dried (Na2SO4) and the solvent removed by evaporation under vacuum to give a yellow oil. Purification by column chromatography (SiO2, 5% MeOH in CH2Cl2), followed by crystallisation from ethyl acetate-hexane, provided the title compound as white crystals (0.62 g, 85%), m.p. 160-162° C. Found: C,61.96; H,6.29; N,16.32. C22H27N5O4 requires C,62.10; H,6.40; N,16.46%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][CH2:27][CH2:28][N:29]=[C:30]=[O:31]>C(O)C.ClCCl>[Cl:26][CH2:27][CH2:28][NH:29][C:30]([NH:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C=NCCCl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Solvent: CCO
Solvent: ClCCl
Product: O=C(NCCCl)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.070 g, 0.200 mmol) in a mixture of ethanol and dichloromethane (1:1, 15 mL) was added 2-chloroethylisocyanate (80.0 μL, 0.79 mmol) in one portion. The mixture was then stirred for 10 minutes at room temperature and then concentrated in vacuo. The residue was washed with 5% HCl solution, water and dried. The residue was purified by column chromatography to afford the title compound in 30% yield (0.028 g). 1H NMR (300 MHz, CDCl3) δ 7.98 (b., s, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.64 (t, J=7.0 Hz, 1H), 7.56 (t, J=7.0 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 7.12 (d, J=10.0 Hz, 1H), 4.99 (m, 1H), 4.06-3.89 (m, 2H), 3.69-3.59 (m, 6H), 3.56-3.53 (m, 2H), 3.47-3.44 (m, 2H), 3.35-3.33 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:27])=[O:26]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(CCCCCCl)NCCO
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCO
Yield: 91.3 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N-(2-hydroxyethyl)-5-chloropentanesulfonamide (459.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfonamide (877.0 mg) as a pale yellow oil (yield: 91.4%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:34]=[CH:33][C:19]([CH:20]=[C:21]([C:29]([O:31][CH3:32])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:17]=1>O1CCCC1.[C].[Pd]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]([C:29]([O:31][CH3:32])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[CH:33][CH:34]=1
Reactant: COC(=O)C(=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 10% palladium carbon (1.1 g) in tetrahydrofuran (4.0 ml) was added a mixed solution of tert-butyl methyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidene]malonate in methanoltetrahydrofuran (2:1, 36.0 ml), and the mixture was stirred at room temperature for 14 hr under hydrogen pressurization (3 atm). After completion of the reaction, the palladium carbon catalyst was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound (5.4 g, quant) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27](O)(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.CN.Cl.C[CH2:35][N:36](C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([NH:36][CH3:35])(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (200 mg, 0.47 mmol, 1.00 equiv) in thionyl chloride (20 mL) was heated under reflux for 3 h, then concentrated under vacuum. The residue was diluted with 10 ml of CH2Cl2 and added dropwise into a solution of MeNH2.HCl (318 mg, 4.75 mmol, 10.00 equiv) and DIEA (917 mg, 7.11 mmol, 15.00 equiv) in CH2Cl2 (20 mL) at 0° C. The resulting solution was stirred for overnight at room temperature, concentrated under vacuum, and purified by Prep-HPLC, yielding 100 mg (49%) of 2,3-bis(4-methoxyphenyl)-N-methylquinoxaline-6-sulfonamide as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH2:18][C:19]([CH3:21])=[CH2:20])([C:15]([OH:17])=[O:16])[CH2:10]1.[Si](C=[N+]=[N-])(C)(C)[CH3:23]>CO>[CH3:23][O:16][C:15]([C@@:11]1([CH2:18][C:19]([CH3:21])=[CH2:20])[CH2:12][C:13](=[O:14])[N:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:10]1)=[O:17]
Reactant: C=C(C)C[C@]1(C(=O)O)CC(=O)N(c2c(C)cccc2C)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: C=C(C)C[C@]1(C(=O)OC)CC(=O)N(c2c(C)cccc2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 105.6 %

Procedure:
To a solution of (S)-1-(2,6-dimethylphenyl)-3-(2-methylallyl)-5-oxo-pyrrolidine-3-carboxylic acid (prepared from c, 430 mg, 1.49 mmol) in MeOH (5 mL) was added TMS-CHN2 (2.24 mL, 4.49 mmol, 2 M solution in hexanes) dropwise. After stirring the yellow colored clear solution at room temperature for 10 min, MeOH was removed under reduced pressure, and the solution was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 solution (25 mL), water (25 mL), brine (25 mL), dried (Na2SO4) and evaporated to obtain (S)-1-(2,6-dimethyl-phenyl)-3-(2-methyl-allyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (474 mg) which was used as such in next step without any further purification. LC-MS: Rt (retention time): 2.14 min, MS: (ES) m/z 302.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][O:9][C:10]1[C:11]([F:31])=[C:12]([F:30])[C:13]2[C:14](=[O:29])[C:15]3[C:20]([O:21][C:22]=2[C:23]=1[F:24])=[C:19]([F:25])[C:18]([OH:26])=[C:17]([F:27])[C:16]=3[F:28].O>C(Cl)Cl>[CH3:8][O:9][C:10]1[C:11]([F:31])=[C:12]([F:30])[C:13]2[C:14](=[O:29])[C:15]3[C:20]([O:21][C:22]=2[C:23]=1[F:24])=[C:19]([F:25])[C:18]([O:26][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:17]([F:27])[C:16]=3[F:28]
Reactant: COc1c(F)c(F)c2c(=O)c3c(F)c(F)c(O)c(F)c3oc2c1F
Reactant: COCCOCCl
Solvent: O
Solvent: ClCCl
Product: COCCOCOc1c(F)c(F)c2c(=O)c3c(F)c(F)c(OC)c(F)c3oc2c1F
Reaction time: 1 h

Procedure:
Methoxyethoxymethyl chloride (150 mg, 1.2 mmol) is added to a solution of Compound 47 in 10 mL dry CH2Cl2 at 20° C. The reaction mixture is stirred for 1 hour and poured into 50 mL water. The product is extracted with diethyl ether (30 mL×2) and ethyl acetate (30 mL). The combined organic extracts are washed with 5% citric acid solution (50 mL), and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield 425 mg yellow oil. The crude oil is then recrystallized from isopropyl alcohol to yield 240 mg (51%) of Compound 48 as a colorless solid. 1H-NMR (d6-DMSO) 5.48 (s, 2H); 4.36 (s, 3H); 3.99 (t, J=Hz, 2H); 3.58 (t, J=Hz, 2H); 3.36 (s, 3H). 19F-NMR (d6-DMSO) 142.90 (d, J=12.7, 1F); 142.97 (d, J=12.4 Hz, 1F); 153.12 (d, J=13.5 Hz, 1F); 155.54 (d, J=19.7 Hz, 1F); 155.82 (d, J=11.3 Hz, 1F); 157.13 (d, J=19.5 Hz, 1F).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCCCCCO
Reactant: CC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)C(C)O
Temperature: 130 °C
Yield: 35.5 %

Procedure:
A 2liter one neck round bottom flask equipped with a Dean Stark trap, condenser and nitrogen inlet/outlet was charged with 150.0 g (1.67 moles) lactic acid, 293.0 g (2.25 moles) octyl alcohol, 6 ml sulfuric acid and 500 ml toluene. Mixture was heated to 130° C. for 6 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. The organic layer was collected and dried over magnesium sulfate. Octyl lactate was distilled under high vacuum to yield 119.9 g (35.6% yield) of clear colorless liquid. According to GC the product is 96.2% pure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:8][OH:9])[NH2:7].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].C>O1CCOCC1.B(F)(F)F.C(OCC)C>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:9][N:8]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[N:7]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=NO)c1cccs1
Agent: C
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2nc(-c3cccs3)no2)cc1
Yield: 65.3 %

Procedure:
To a solution of 2-thiopheneamidoxime (10 g, 0.07 mole) and p-nitrobenzoyl chloride (13 g, 0.07 mole) in 400 ml of dry dioxane, 1 ml of BF3 -ethyl ether is added and the mixture is heated to reflux for 16 hours. Evaporation of the solvent in vacuo gives a dark solid. It is decolorized by treating with Darco (CHCl3). The solvent is concentrated in vacuo and the product is crystallized from ethanol to give 12.5 g (65%) of product, m.p. 169°-171°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C/c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(/C=C/c2ccccc2)cc1
Temperature: -5 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
To 210 mg (1 mmol) of (E)-4-methoxystilbene (4b) in 7 mL of CH2Cl2 was added 1.28 mL of 1M BBr3 (1.3 mmol) in dichloromethane at −10° C. The mixture was stirred for 4 h at −5° C. and quenched by pouring into cold water. The product was extracted with CH2Cl2, dried over anhydrous MgSO4 and chromatographed using 1:10 CH3OH:CH2Cl2 to afford 85 mg (43%) of 4a. mp 184-185° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[CH2:16]([SH:19])[CH2:17][SH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[S:18]1[C:12]2([CH2:13][CH2:14][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[OH:1])[CH2:10][CH2:11]2)[S:19][CH2:16][CH2:17]1
Reactant: SCCS
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(C2CCC3(CC2)SCCS3)c(O)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added 4-(2,4-dihydroxyphenyl)cyclohexanone (1 g) and toluene (40 ml). To the stirred solution was added ethane-1,2-dithiol (0.49 ml) and a few crystals of p-toluenesulfonic acid monohydrate and the reaction mixture was heated under reflux for 3.5 hr. The reaction mixture was cooled to room temperature, saturated sodium hydrogencarbonate solution (20 ml) was added, and the layers were separated. The aqueous layer was diluted with water (40 ml) and extracted into ethyl acetate (3×30 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether 2:3 v/v) furnished the title compound (1.34 g, 98%) as a white solid. δH (CD3OD): 1.59-1.73 (2H, m), 1.75-1.84 (2H, m), 1.98-2.08 (2H, m), 2.14-2.22 (2H, m), 2.77 (1H, tt), 3.22-3.32 (4H, m), 6.18-6.24 (2H, m), 6.85 (1H, d); m/z (ES+) 283 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:21])[C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[C:15]([CH3:19])[C:16]([CH3:18])=[CH:17][C:8]=3[NH:7][C:6]=2[N:20]=1.[H-].[Na+].[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29]Cl)[CH3:25]>CN(C)C=O>[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][N:7]1[C:8]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[C:4]([CH3:21])=[CH:3][C:2]([CH3:1])=[N:20][C:6]1=2)[CH3:25]
Reactant: Cc1cc(C)c2c(n1)Nc1cc(C)c(C)cc1N(C)C2=O
Reactant: CCN(CC)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCN1c2cc(C)c(C)cc2N(C)C(=O)c2c(C)cc(C)nc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 1.8 mg of 6,11-dihydro-2,4,6,8,9-pentamethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 30 ml of dimethyl formamide and 0.34 gm of 50% sodium hydride in mineral oil was stirred in a nitrogen atmosphere at 50° C. for 30 minutes. Then, a solution of 1.5 gm of 3-diethylaminopropyl chloride in 15 ml of dimethyl formamide was added dropwise at room temperature, and the mixture was heated on an oil bath at 120° C. for 2 hours and then evaporated in vacuo. The residue was admixed with dilute ammonia, and the mixture was repeatedly extracted with ether. The combined ether extracts were dried with sodium sulfate, the ether was distilled off, and the residue was recrystallized from petroleum ether (m.p. 100°-140° C.), yielding 53% of theory of the compound named in the heading, which had a melting point of 104°-106° C.