Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:20]=[N:21][N:22]([CH2:24][CH2:25][CH2:26]Br)[N:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[CH3:32][S:33]C.[Na].O.C(OCC)(=O)C>CS(C)=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:20]=[N:21][N:22]([CH2:24][CH2:25][CH2:26][S:33][CH3:32])[N:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(COc2ccc(Cc3nnn(CCCBr)n3)cc2)ccc(C(C)=O)c1O
Reactant: CSC
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(COc2ccc(Cc3nnn(CCCSC)n3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-bromopropyl)-2H-tetrazole (3.1 g, 0.006 mol) was dissolved in DMSO (20 ml). A large excess of sodium methyl sulfide was added and the reaction mixture was stirred at room temperature for three hours. Water (100 ml) was added and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a mixture of 9:1 toluene:ethyl acetate) to yield 2.1 g, 77.8% yield of the title product as a yellow oil which crystallized upon standing: n.m.r. (300 MHz, CDCl3) δ: 1.0 (t, 3H); 1.6 (m, 2H); 2.1 (s, 3H); 2.3 (m, 2H); 2.5 (m, 2H); 2.6 (s, 3H); 2.7 (t, 2H); 4.2 (s, 2 H); 4.7 (t, 2H); 5.1 (s, 1H); 6.9 (d, 2H); 7.0 (d, 1H); 7.3 (d, 2H); 7.6 (d, 1H); 12.7 (s, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:16]=[CH:15][C:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[C:5](C)[CH:4]=1.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Br:28])[CH:22]=1)=O>O1CCCC1.BrCCBr>[Br:28][C:23]1[CH:22]=[C:21]([C:19]([C:3]2[CH:4]=[CH:5][C:6]([O:7][Si:8]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10])=[CH:15][CH:16]=2)=[CH2:18])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: Cc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a mixture of magnesium turnings (1.5 g, 0.06 mol, 1.2 eq) in dry tetrahydrofuran (10 mL), was added a portion (⅕) of (4-bromo-2-methyl-phenoxy)-tert-butyl-dimethyl-silane (16.0 g. 0.05 mol, 1.1 eq) in dry tetrahydrofuran (50 mL) and 1,2-dibromoethane (0.5 mL). The resulting solution was refluxed and the other (⅘) portion of the above solution was added and the resulting solution was refluxed for 2 h. After cooled at 0° C. a solution of 3-bromo-4-fluoroacetophenone (11.5 g, 0.05 mol, 1 eq) in dry tetrahydrofuran (40 mL) was added dropwise and the reaction was stirred for 3 h at room temperature. The mixture was quenched with saturated ammonium chloride solution (20 mL). The aqueous phase was extracted with dichloromethane (3×20 mL), dried (sodium sulfate) and the solvent removed in vacuo. The crude latter was dissolved in toluene (200 mL) and a catalytic amount (30 mg) of p-toluenesulfonic acid was added and refluxed for 3 h. The solvent was removed and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colourless oil (18.5 g, 39%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20](C(O)=O)[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4]CC1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O.CC(C)=O>[N:17]1([C:14]2[N:15]=[CH:16][C:11]([N:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)=[CH:12][CH:13]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH2:19][CH2:18]1
Reactant: O=C(O)N1CCN(c2ccc(N3CCC4(CC3)OCCO4)cn2)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 150-ml flask, 5.51 g of tert-butyl ester of 4-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid (intermediate 7.1) is put in 21 ml of tetrahydrofuran, 21 ml of water and 20 ml of acetone. It is cooled on an ice bath and 8.24 ml of 95% sulfuric acid is added gently. It is stirred at room temperature for 18 h. The solution is then poured into water. 5N sodium hydroxide is added to basic pH and it is extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The raw product obtained is chromatographed on silica gel, eluting with a gradient of ternary solvents, on the one hand heptane and on the other hand heptane/ethyl acetate/methanol 4/5/1 varying from 10% to 100%. 2.39 g of 6′-(3,4-dihydro-2H-quinoxalin-1-yl)-2,3,5,6-tetrahydro-[1,3′]bipyridinyl-4-one is obtained.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]3)[CH:12]=2)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].[CH2:26](I)[CH3:27].C(N(CC)CC)C>CN(C)C=O>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:26][CH3:27])[CH:16]([CH3:20])[CH2:15]3)[CH:12]=2)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3]
Reactant: CCI
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CC1C
Yield: 48.1 %

Procedure:
A solution of 1.00 g of 1-ethyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid hydrochloride, 1.29 g of ethyl iodide and 1.09 g of triethylamine in 20 ml of N,N-dimethylformamide was heated at 70° to 80° C. for 1.5 hours. The solvent of the reaction mixture was evaporated and the residue was acidified with 50% aqueous acetic acid. The solution was neutralized with 20% aqueous sodium hydroxide and the precipitate was filtered. The precipitate was chromatographed on silica gel using chloroform-methanol (9:1) as eluent to give 0.47 g of the title compound as colorless crystalls, which was recrystallized from a mixture of chloroform and methanol as colorless needles, M.p. 203°-205° C.
Reaction SMILES: O.[CH2:2]([NH:9][CH:10]([CH3:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C1C=CC=CC=1>[CH2:2]([N:9]([CH:10]([CH3:12])[CH3:11])[C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)NCc1ccccc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)N(Cc1ccccc1)C(=O)C(C)(C)C

Procedure:
A one-liter reaction flask fitted with a power stirrer, heating mantle, dropping funnel, thermometer, water-cooled condenser and drying tube was charged with 149.2 g (1.0 mole) N-benzyl-N-isopropylamine, 350 ml of benzene and 111.1 g (1.1 mole) of triethylamine. The dropping funnel contained 126.6 g (1.05 mole) of pivalyl chloride which was added dropwise to the stirred reaction mixture. After the addition was completed, the reaction mixture was stirred and heated at 75-80° for 18 hours. The mixture was cooled and the amine-salt was collected on a vacuum filter. The filtrate was transferred to a separatory funnel and extracted with water which was followed by dilute aqueous hydrochloric acid. The organic phase was dried over sodium sulfate. After removing the drying agent, the solvent was evaporated. The liquid residue was transferred to a pot which was appropriately fitted for a simple vacuum distillation. The forecut material proved to be mainly trimethylacetyl chloride and trimethylacetic acid. The product fraction weighed 188.6 g, b.p. 86-87/0.07 mm, nD25 1.5074.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([CH2:15][O:16]COC)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.O.C(OCC)(=O)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCOCc1cnnc(-c2ccc(F)c(Cl)c2)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCc1cnnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
3-(3-Chloro-4-fluoro-phenyl)-5-methoxymethoxymethyl-pyridazine (0.06 g, 0.21 mmol) was dissolved in dioxane (2 ml) and treated with 1N HCl (0.2 ml, 0.2 mmol). The reaction mixture was refluxed for 1.5 hours then cooled to room temperature. Water and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 1:1 then 2:8) to provide [6-(3-chloro-4-fluoro-phenyl)-pyridazin-4-yl]-methanol (13 mg, 26%) as a light yellow solid, MS: m/e=239.2 (M+H+).
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([NH:21][C:22]([CH3:23])=[O:24])=[N:19][CH:20]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1
Product: CC(=O)Nc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1
Temperature: 25 °C
Yield: 60 %

Procedure:
5-(6,7-Dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)pyridin-2-amine 142 (60 mg, 0.2 mmol) was heated in 1 ml of acetic anhydride at 85° C. for 60 min. The reaction mixture was then cooled to room temperature, the precipitate filtered out, washed with cold ethanol and dried in high vacuum to yield 308 (44 mg, 60%). MS: (ESI+) 338.1
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:3]=O.N1CCCCC1.[C:18]([CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])#[N:19].C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[C:20]([C:18]#[N:19])=[CH:3][C:2]([CH3:11])([CH3:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#CCC(=O)OCc1ccccc1
Reactant: CC(C)CCCC(C)(C)C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)CCCC(C)(C)C=C(C#N)C(=O)OCc1ccccc1
Yield: 61.6 %

Procedure:
To a mixture of 2,2,6-Trimethyl-heptanal (1.05 g, 6.73 mmol), piperidine (0.19 mL, 2.01 mmol) and benzyl cyanoacetate (1.29 g, 7.4 mmol) in toluene (50 mL) was added glacial acetic acid (0.72 g, 12.1 mmol). The flask was fitted with a Dean-Stark trap, and the mixture was heated at reflux for 18. The mixture was cooled, treated with dilute HCl, and the layers were separated. The organics were washed with a saturated sodium bicarbonate solution followed by brine, and dried (MgSO4), filtered and concentrated. The residual oil was purified by silica gel chromatography (98/2 hexane/EtOAc) to give 1.3 g of 2-Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester m/z 314 (M+).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.C1C=C([N+:19]([O-:21])=[O:20])C(OC2OC(CO)C(O)C(O)C2O)=CC=1.[OH2:34]>C([O-])([O-])=O.[Na+].[Na+]>[N+:19]([O:21][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:34])=[O:20]
Reactant: O
Reactant: O=[N+]([O-])c1ccccc1OC1OC(CO)C(O)C(O)C1O
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])Oc1ccccc1
Reaction time: 0.5 h

Procedure:
After the culture, each 1 ml of culture medium was added 15 μl of toluene and shaked at 37° C. for 30 minutes. After shaking, the culture medium was diluted 10 to 100 times in order to measure the produced amount of β-galactosidase. One ml of the solution was taken out and shaked at 30° C. for 5 minutes, followed by addition of 3.5 ml of 0.2M phosphate buffer (pH 7.25) and 0.5 ml of 0.01M O-nitrophenyl-β-D-galactopyranoside (ONPG) and 10 minutes' shaking. After sampling 1 ml of the solution and stopping the reaction by placing it in 1M Na2CO3, 8 ml of water was added thereto so as to make the whole amount 10 ml. The absorbance of this sample was measured at 420 nm by using a spectrophotometer. The amount of O-nitrophenol (ONP) produced was calculated from the standard curves of ONT. In this case, the β-galactosidase activity for decomposing 1 μmole of ONPG per minute was defined as one unit (U).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1.[Br:16]Br>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([CH3:12])=[C:8]([O:10][CH3:11])[C:9]=1[Br:16]
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(C)c(OC)c1Br
Reaction time: 5 h
Yield: 95 %

Procedure:
3,5-Dimethoxy-4-methyl-benzoic acid methyl ester (1 mmol) was taken in 2 mL of dichloromethane, and a solution of bromine (1 mmol) in 0.5 mL of dichloromethane was added from a pressure-equalizing dropping funnel at room temperature over a period of 1.5 h. A NaOH trap system was provided on top of the addition funnel. The mixture was then stirred for 5 h and the solvent was evaporated off to give 2-Bromo-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Br:12])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.Cl[C:37](OCC)=[O:38]>O1CCCC1.CN(C)C=O>[Br:12][C:5]1[C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]2[NH:1][C:37](=[O:38])[N:13]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:3]=2[CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(C(F)(F)F)cc2N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)c(Br)cc32)CC1
Reaction time: 1.5 h
Yield: 93 %

Procedure:
A stirred solution of 1,1-dimethylethyl 4-{[2-amino-5-bromo-4-(trifluoromethyl)phenyl]amino}-1-piperidinecarboxylate (D67, 0.98 g, 2.2 mmol) in tetrahydrofuran (25 ml) at room temperature under argon was treated with diisopropylethylamine (0.78 ml, 4.4 mmol) followed by ethyl chloroformate (0.24 ml, 2.5 mmol) and maintained for 20 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated under vacuum to leave a beige solid, which was dissolved in dimethylformamide (20 ml) and heated with stirring under argon for 1.5 hrs. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated under vacuum to afford the title compound as a light brown solid (0.95 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])[C:5]([N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])=[O:6].CN([Si](C)(C)C)[C:19](=[O:24])[C:20](F)(F)F.[C:29](OCC)(=[O:31])[CH3:30]>>[C:19]([O:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][C:29](=[O:31])[CH3:30])[C:5]([N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])=[O:6])(=[O:24])[CH3:20]
Reactant: CCOC(C)=O
Reactant: O=C1NCCN1C(=O)c1ccc(O)c(O)c1
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Product: CC(=O)Oc1ccc(C(=O)N2CCNC2=O)cc1OC(C)=O
Reaction time: 0.5 h

Procedure:
1-(3,4-Dihydroxybenzoyl)-2-imidazolidinone (2.2 g, 0.01 mol) was suspended in 70 ml of ethyl acetate. To the suspension was added 6.1 ml (0.033 mol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide with stirring. After 30 minutes, a clear solution was formed (solution A).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([CH3:15])=[N:13][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([CH3:15])=[N:13][N:14]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([C:21](=[O:22])[C:20]4[CH:31]=[CH:32][C:17]([Cl:16])=[CH:18][CH:19]=4)=[CH:30][CH:29]=3)[C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1n[nH]c2cnn(C(C)(C)C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c2cnn(C(C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (10 ml) was dissolved 5-t-butyl-3-methyl-1H-pyrazolo [3,4-d]pyridazin-4(5H)-one (516 mg) followed by addition of 4-(4-chlorobenzoyl)benzyl bromide (1.2 g) and potassium carbonate (525 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with ethyl acetate-THF and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=1:1), washed with n-hexane-diethyl ether, and dried. White powder, 527 g.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[H][H].Cl[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH3:35]>CN(C=O)C.O>[CH2:33]([C:20]1[N:19]([CH2:18][CH2:17][O:16][CH2:15][CH2:14][CH2:13][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=1)[CH2:34][CH3:35]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCCl
Reactant: [H][H]
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCSc1ccccn1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Under a nitrogen atmosphere 2-mercaptopyridine (1.23 g, 11.1 mmol) was added to a suspension of sodium hydride (0.41 g of 60%, 10 mmol) in DMF (30 mL). After hydrogen evolution had ceased, 1-[2-(3-chloropropoxy)ethyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (3.20 g, 9.23 mmol) was added. After 2 hours analysis by HPLC indicated that starting material remained. 2-Mercaptopyridine (0.30 g) and sodium hydride (0.10 g) were added. After 3.5 hours the reaction mixture was poured into water with rapid stirring. The resulting brown solid was isolated by filtration and then triturated with diethyl ether to provide 3.71 g of 2-propyl-1-(2-{3-[(pyridin-2-yl)thio]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:17]=3[CH2:16][O:15][C:14]=2[CH:26]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[CH:31](OC)(OC)OC.C(O)(=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][C:23]([N:25]4[CH:31]=[N:29][N:28]=[N:27]4)=[CH:24][C:17]=3[CH2:16][O:15][C:14]=2[CH:26]=1
Reactant: COC(OC)OC
Reactant: Nc1ccc2c(c1)COc1cc(Nc3ccc(F)cc3F)ccc1C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1c2ccc(-n3cnnn3)cc2COc2cc(Nc3ccc(F)cc3F)ccc21
Temperature: 100 °C

Procedure:
0.015 g (0.042 mmol) of (8) and 0.01 g (0.15 mmol) of sodium azide are suspended in 0.05 g (0.33 mmol) of trimethyl orthoformate at 0° C. 0.03 g (0.50 mmol) of glacial acetic acid is then added to the mixture and the mixture is heated to 100° C. and refluxed for 4 h. After cooling to room temperature, the mixture is concentrated in vacuo and the residue is taken up with EtOAc and dissolved under the influence of heat. The yellow product precipitates out in the cold.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].CO.Cl[CH2:21][N:22]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[CH:34]([CH3:36])[CH3:35])[S:23]1(=[O:25])=[O:24]>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([O:10][CH2:21][N:22]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[CH:34]([CH3:36])[CH3:35])[S:23]1(=[O:24])=[O:25])=[O:9]
Reactant: CC(C)c1cccc2c1C(=O)N(CCl)S2(=O)=O
Reactant: O=C(O)c1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)c1cccc2c1C(=O)N(COC(=O)c1c(Cl)cncc1Cl)S2(=O)=O
Product: Cl
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
A mixture of 3,5-dichloro-4-pyridinecarboxylic acid (0.42 g, 0.002 mol), cesium carbonate (0.36 g, 0.001 mol) and methanol (10 ml) was stirred for 30 minutes. The solvent was removed in vacuo and 2-chloromethyl-4-isopropylsaccharin (0.55 g, 0.002 mol) and DMF (10 ml) were added to the residue. The mixture was heated to 75° C. and stirred for 3 hours. The solvent was removed in vacuo and the residue was partitioned between water/methylene chloride. The organic layer was separated, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was treated with ethereal HCl to afford a white gum which was triturated with Et2O (2X), then acetone. A white solid was obtained which was collected by filtration and dried in high vacuum to afford 0.14 g (15%) of 4-isopropyl-2-saccharinylmethyl 3,5-dichloro-pyridine-4-carboxylate hydrochloride, m.p. 93°-95° C.
Reaction SMILES: [C:1]1([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH3:33])[CH:26]=1)[NH2:24].C(OCC)(=O)C.CCCCCC>C(O)C>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([C:1]3[CH2:5][CH2:4][CH2:3][CH:2]=3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:24]2)=[CH:26][C:27]=1[CH3:33])#[N:30]
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1=CCCC1)C2=O
Reactant: Cc1cc(NN)ccc1C#N
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OCC1C2=NN(c2ccc(C#N)c(C)c2)C1C1=CCCC1
Temperature: 80 °C
Yield: 33 %

Procedure:
To a suspension of methyl 3-(cyclopentenylmethylene)-4-oxochroman-7-carboxylate; Preparation 34 (260 mg, 0.92 mmol) in ethanol (7 mL) was added 4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 (218 mg, 1.2 mmol). The slurry was heated to 80° C. for eighteen hours. The solution was returned to ambient temperature and the resulting solid was collected by vacuum filtration and washed with cold ethanol. Chromatography (normal phase, ethyl acetate/hexane) provided largely the cis isomer of methyl 2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate (yellow solid, 125 mg, 33% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.98 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 414 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.83 (m, 2H), 2.05-2.11 (m, 2H), 2.14-2.20 (m, 2H), 2.39 (s, 3H), 3.83 (s, 3H), 3.88 (dd, J=13.02, 10.34 Hz, 1H), 3.98-4.03 (m, 1H), 4.67 (dd, J=10.20, 5.64 Hz, 1H), 5.45 (d, J=11.01 Hz, 1H), 5.60 (br. s., 1H), 6.86 (br. s., 1H), 7.11 (br. s., 1H), 7.44 (d, J=1.34 Hz, 1H), 7.53 (d, J=8.59 Hz, 1H), 7.58 (dd, J=8.06, 1.61 Hz, 1H), 7.93 (d, J=8.06 Hz, 1H).