Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[F:9][C:10]1[CH:11]=[C:12]([C:45]2[C:46]([C:51]#[N:52])=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:13]=[C:14]([F:44])[C:15]=1[CH2:16][N:17]1[C:22]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:21]=2[C:20](=[O:31])[N:19]([CH2:32][C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)=[O:34])[C:18]1=[O:43].[N:53]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[F:9][C:10]1[CH:11]=[C:12]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[NH:53][C:4](=[O:7])[O:5][N:52]=2)[CH:13]=[C:14]([F:44])[C:15]=1[CH2:16][N:17]1[C:22]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:21]=2[C:20](=[O:31])[N:19]([CH2:32][C:33]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)=[O:34])[C:18]1=[O:43]
Reactant: COc1ccc(C(=O)Cn2c(=O)c3cc(CC(F)(F)F)sc3n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2=O)cc1
Reactant: O=C([O-])O
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cn2c(=O)c3cc(CC(F)(F)F)sc3n(Cc3c(F)cc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2=O)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A mixture of hydroxylammonium chloride (0.56 g), sodium hydrogencarbonate (0.81 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′,5′-difluoro-4′-{[3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (30 mL), N,N′-carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue were added 25% sulfuric acid (5 mL) and 1-butanol (5 ml), and the mixture was stirred at 100° C. for 1 hr. The precipitated solid was collected by filtration to give the title compound as a colorless amorphous solid (0.15 g, 26%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[SH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[S:18][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: Sc1cccs1
Reactant: O=C1CCOc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCOc2cc(Sc3cccs3)ccc21
Temperature: 78 °C
Yield: 92.4 %

Procedure:
7-Bromochroman-4-one (1.5 g, 6.6 mmol), thiophene-2-thiol (0.68 mL, 7.3 mmol), and potassium carbonate (1.37 g, 9.9 mmol) were combined in ACN (50 mL) in a sealed vessel, and the reaction was heated at 78° C. overnight. The reaction was cooled, filtered, and concentrated. Purification by silica gel chromatography (10-60% EtOAc/hexanes) gave 1.6 g (93%) of the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 2.75 (2H, t, J=6.4 Hz), 4.48 (2H, t, J=6.4 Hz), 6.59 (1H, d, J=1.8 Hz), 6.75 (1H, dd, J=8.4, 1.8 Hz), 7.13-7.17 (1H, m), 7.34 (1H, dd, J=3.6, 1.2 Hz), 8.58 (1H, dd, J=5.4, 1.2 Hz), 7.75 (1H, d, J=8.4 Hz). [M+H] calc'd for C13H10O2S2, 263. found 263.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16](OC)(=[O:27])[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C[O-].[Na+].Cl>O.CN(C)C=O>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:17]([C:16](=[O:27])[CH2:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:11]=2)=[O:15])=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCCCCOc1ccc(C(C)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.6 %

Procedure:
Dimethylformamide (600 ml), p-pentyloxyacetophenone (60.0 g) and dimethyl terephthalate (73.5 g) were charged in 1-liter three-necked flask and stirred. To this mixture was added 28% methanolic solution (84.2 g) of sodium methoxide and, after that, a reaction was carried out at the inner temperature of 35 to 40° C. for 48 hours. After completion of the reaction, the reaction solution was added to a mixed solution of water (3,000 ml) and 1N hydrochloric acid (600 ml) to separate the crystals. The mixture was stirred at room temperature for 1 hour, and then the separated crystals were filtered. The wet crystals and methanol (1,000 ml) were charged in a 2-liter three-necked flask, heated to reflux for 2 hours and cooled down to room temperature, and the crystals were filtered. The crystals were washed with methanol (200 ml). The crystals were dried overnight in vacuo to give 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)-propane-1,3-dione (66.0 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:25][CH2:26]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Product: CC(=O)NC1(c2ccc(CN3CCN(c4nccs4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in Example 71(1) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(thiazol-2-yl)piperazine obtained in Example 81(1) instead of phenylpiperazine, the title compound was obtained as pale-yellow crystals, m.p.=184-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19](O)=[O:20])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.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.[C:55]([NH2:64])(=[O:63])[C:56]1[C:57](=[CH:59][CH:60]=[CH:61][CH:62]=1)[NH2:58]>ClCCl.CC#N>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]([NH:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[C:55]([NH2:64])=[O:63])=[O:20])[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1ccc(S(=O)(=O)N2CCN(CC(=O)O)CC2)cc1
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: CC#N
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCN(CC(=O)Nc3ccccc3C(N)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of [4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-acetic acid (1.10 g, 3.5 mmol), HATU (1.33 g, 3.5 mmol) and DIEA (1.22 mL, 7 mmol) in dichloromethane (40 mL) was added anthranilamide (714 mg, 5.25 mmol). The reaction was stirred at room temperature for 1 hour and then the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (50-100% ethyl acetate-hexanes) to yield the pure product. (1.18 g, 78%). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 7.77 (d, J=7.0 Hz, 2H), 7.51 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 7.05 (d, J=7.1 Hz, 2H), 6.10 (br s, 1H), 5.51 (br s, 1H), 3.92 (s, 3H), 3.24 (m, 6H), 2.76 (t, J=4.7 Hz, 4H); HPLC ret. time 2.46 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 433.1 (M+1)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].CC(O)=O>C1(C)C=CC=CC=1>[C:13]([C:15](=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCCC(C(=O)OCC)C1
Yield: 73.3 %

Procedure:
Into a 500-mL round-bottom flask, was placed ethyl 3-oxocyclohexane-1-carboxylate (7 g, 41.13 mmol, 1.00 equiv), ethyl 2-cyanoacetate (6.5 g, 57.46 mmol, 1.40 equiv), AcOH (0.8 mL) and NH4OAc (300 mg) in toluene (150 mL). The resulting solution was heated to reflux overnight in presence of a Dean-Stark. After the starting 4 was consumed completely, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to give the corresponding ethyl 3-(1-cyano-2-ethoxy-2-oxoethylidene)cyclohexane-1-carboxylate (8.0 g, 73%) as yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[C:28]1([S:34]([OH:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C>CC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O-:37])(=[O:36])=[O:35]
Reactant: O=S(=O)(O)c1ccccc1
Agent: OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=S(=O)([O-])c1ccccc1
Temperature: 42.5 °C
Reaction time: 3 h

Procedure:
Quetiapine free base (5.0 g) was dissolved in acetone (50 ml) at room temperature. This was followed by the addition of benzene sulfonic acid (2.0 g) at 30 to 35° C. The resulting mass was heated at 40-45° C. and maintained for 30 minutes. The resulting mass was cooled at 25-30° C. This was followed by the addition of diethyl ether (50 ml) and stirred for 3 hours. The precipitated product was collected by filtration under nitrogen and washed with diethyl ether (25 ml) and dried under vacuum to give the title compound as off white powder (5.94 g).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8](=[O:11])[CH2:9][CH3:10])[C:6](=[O:12])[CH2:5][CH:4]([C:13]#[N:14])[CH2:3]1.[CH2:15]([SH:17])[CH3:16].[ClH:18]>C(OCC)C>[ClH:18].[O:12]=[C:6]1[CH:7]([C:8](=[O:11])[CH2:9][CH3:10])[C:2](=[O:1])[CH2:3][CH:4]([C:13]([S:17][CH2:15][CH3:16])=[NH:14])[CH2:5]1
Reactant: CCS
Reactant: CCC(=O)C1C(=O)CC(C#N)CC1=O
Agent: Cl
Solvent: CCOCC
Product: CCSC(=N)C1CC(=O)C(C(=O)CC)C(=O)C1

Procedure:
19.3 g (0.1 mol) of 3,5-dioxo-4-propionylcyclohexanecarbonitrile and 6.5 g (0.105 mol) of ethyl mercaptan were dissolved in 800 ml of dry diethyl ether and reacted with hydrogen chloride as described in Example 2.1: 20.7 g (71% of theory) of compound 2.2 [melting point 180°-185° C. (decomposition)].
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[CH2:7](O)[CH2:8][CH2:9][CH3:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[O:3]
Reactant: CCCCO
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 70.1 %

Procedure:
First, a toluene (1 L) solution of pyruvic acid (440 g, 5.0 mol), n-butanol (371 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours while removing water under a nitrogen gas stream, whereby a first reaction solution was obtained. Next, the first reaction solution was cooled to room temperature (25° C.). Thereafter, toluene was removed under reduced pressure (40 mmHg) using an evaporator, and the residue was purified by reduced pressure distillation (40 mmHg, 93 to 100° C.), whereby butyl pyruvate (505 g, yield 70%) was obtained.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.[NH:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[C:26]=2[CH:25]=[CH:24]1>>[C@H:14]1([NH:13][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[C:27]3[CH:28]=[CH:29][CH:30]=[C:31]4[C:26]=3[CH:25]=[CH:24][NH:23]4)[N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: N[C@@H]1CCc2ccccc21
Product: c1ccc2c(c1)CC[C@H]2Nc1ccc2c(-c3cccc4[nH]ccc34)cccc2n1

Procedure:
The title compound, MS: m/e=376.5 (M+H+), was prepared in accordance with the general method of example 63 from 5-iodo-2-chloroquinoline, (R)-1-aminoindane and 1H-indole-4-boronic acid.
Reaction SMILES: C1([Li])C=CC=CC=1.[Br:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>CCOCC.O1CCCC1>[Br:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=1)=[O:20]
Reactant: Brc1ccsc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C(=O)c2sccc2Br)c1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
A solution of phenyllithium (210 ml, 2.1M in cyclohexane) was added dropwise to a solution of 66 g of 3-bromothiophene in 400 ml of anhydrous ether at 5° C. The entire process was conducted under nitrogen. After the addition, the solution was stirred overnight under nitrogen. The resultant solution was then added dropwise to a solution of m-methoxybenzoyl chloride (90 g) in 600 ml of tetrahydrofuran at -70° C. over two hours and thereafter stirring was continued for two hours at the same temperature. The reaction was then quenched with water, the organics were extracted into ether, and the ether phase was washed with 10% sodium hydroxide solution and water, and dried over anhydrous magnesium sulfate. Upon evaporation of the solvent, an oily liquid was obtained which was chromatographed over alumina. Elution with hexane and thereafter with 10%, 20% and 50% ether/hexane gave 89.1 g of an oil which was vacuum distilled.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O.[NH2:14][NH2:15]>O1CCOCC1>[Cl:12][C:5]1[N:4]=[N:3][C:2]([NH:14][NH2:15])=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=1
Reactant: NN
Reactant: CS(=O)(=O)c1cc(Cl)nnc1Cl
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(Cl)nnc1NN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,6-Dichloro-4-methanesulfonylpyridazine (W4.126; 660 mg, 2.9 mmol) was dissolved in 1,4-dioxane (5 ml) and hydrazine hydrate (295 μl, 5.8 mmol) was added. The mixture was stirred at RT for 4 h, then concentrated, and the residue was purified by flash chromatography (dichloromethane:ethyl acetate). Yield: 200 mg
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:28]1[C:29]([N+:35]([O-:37])=[O:36])=[C:30](O)[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1CCCCC1.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:23]1[CH2:22][O:21][C:18]2([CH2:19][CH2:20][C:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)([C:25]#[C:26][C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:35]([O-:37])=[O:36])[CH:28]=3)[CH2:16][CH2:17]2)[O:24]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Reactant: O=[N+]([O-])c1c(O)cccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1ccc(C2(C#Cc3cccc([N+](=O)[O-])c3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Temperature: 70 °C

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.14 g, 0.38 mmol) and 3-iodonitrophenol (0.10 g, 0.38 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.02 g, 4%), copper(I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine. After heating at 70° C. for 0.33 h, the mixture was diluted with dichloromethane, was washed with 1N hydrochloric acid, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 1,1-(ethylenedioxy)-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-nitrophenylethynyl)cyclohexane as an orange wax. 1H-NMR (400MHz, CDCl3) δ 8.29 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.26 (d, J=2 Hz, 1H), 7.14 (dd, J=8.3, 2 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.82 (m, 1H), 4.01 (s, 4H), 3.85 (s, 3H), 2.18 (m, 4H), 2.07 (m, 2H), 1.93 (m, 4H), 1.85 (m, 4H), 1.6 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:12][O:13][C:14](=[O:35])[CH:15]=[CH:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: O=Cc1ccc2[nH]cnc2c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)C=Cc1ccc2[nH]cnc2c1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To a solution of 1H-benzoimidazole-5-carboxaldehyde (250 mg in 12 mL dry tetrahydrofuran) at 0° C. was added 1.43 g methyl(triphenylphosphoranylidene)acetate and the mixture allowed to warm to room temperature. After 24 hours the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 93:7) to give the title compound (257 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:28]([O:31][CH2:32][CH2:33]Cl)[CH2:29][CH3:30].CO>CN(C)C=O.O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][CH2:32][O:31][CH2:28][CH2:29][CH3:30])[C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCOCCCl
Reactant: CCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCCOCCn1c(=O)c2c(ncn2Cc2ccccc2)n(CCC)c1=O
Reaction time: 1 h

Procedure:
1.7 g (12.48 mmol) of potassium carbonate were added at 60° C. to a suspension of 2.2 g (7.8 mmol) of 7-benzyl-3-propylxanthine (prepared according to Example 4a) in 70 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 1.3 ml (10.14 mmol) of 2-propoxyethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 10 hours. 1.2 ml of methanol and 14 ml of water were then added, and the mixture was allowed to stand overnight, treated with a further 70 ml of water and extracted three times using 84 ml of methyl tert-butyl ether each time. The combined organic phases were washed twice with 42 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethae/methanol (19/0.1).
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.C(O)=O>C(N(CC)CC)C>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:21]=[CH:20][C:17]=1[O:18][CH3:19]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1OC
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were weighed to 40 ml of the mixture of formic acid and triethylamine recovered by distillation in Example 3. The reaction was carried out and the final product was separated as described in Example 3. The volume of the mixture of formic acid and triethylamine recovered amounted to 28 ml.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O-]CC.[Na+].[Na].[CH3:22][C@@H:23]1[O:25][C@H:24]1[CH3:26]>C(O)C>[CH3:13][C:12]([C:7]1[CH:8]=[C:9]([S:11][CH:23]([CH3:22])[CH:24]([OH:25])[CH3:26])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C[C@@H]1O[C@H]1C
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (18.2 g, 0.076 mole) was added to a solution of sodium ethoxide freshly prepared from sodium (3.5 g, 0.15 mole) in ethyl alcohol (100 ml) and stirred for 1 hour. After cooling to 5° C. with an ice bath, trans-2,3-epoxybutane (5.0 g, 0.069 mole) was added and the ice bath removed. After stirring for 5.5 hours the reaction mixture was poured into ten percent hydrochloric acid (50 ml). The ethyl alcohol was removed using a rotary evaporator and the aqueous residue extracted with ethyl acetate (2×75 ml). The extracts were combined, dried over sodium sulfate, filtered, and concentrated to an orange oil. The product was purified by chromatography on silica to give a yellow solid which was recrystallized from hexane to give a white solid, m.p. ca. 73° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 43 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (76 mg, 0.14 mmol), 3-tributylstannanyl-pyridine (0.068 mL, 0.21 mmol) and PdCl2(PPh3)2 (20 mg, 0.029 mmol) in 4 mL of DMF was heated at 120° C. for 2.5 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH) to give 32 mg of the title compound as a tan solid. MS: (+) m/z 532.30 (M+1).