Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:8]2[CH:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](NC(=O)CC4C=CC(F)=CC=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:44]=[CH:43][CH:42]=[C:41](C(O)=O)[C:40]2=[O:48])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[ClH:1].[NH2:2][C:3]1[C:8]2[CH:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:41]4[C:40](=[O:48])[N:39]([C:36]5[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=5)[CH:44]=[CH:43][CH:42]=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: Nc1nccc2c1ccn2-c1ccc(NC(=O)NC(=O)Cc2ccc(F)cc2)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc2c1ccn2-c1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Reaction time: 8 h
Yield: 14.7 %

Procedure:
Bis-tert-butyl 1-(4-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl-dicarbamate (Compound B of Example 3, 0.18 g, 0.043 mmol, 1.0 eq) was added to a solution of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.011 g, 0.047 mmol, 1.1 eq) and TBTU (0.018, 0.047 mmol, 1.1 eq) in DMF (0.50 mL) at room temperature. Diisopropylethylamine (0.008 mL, 0.047 mmol, 1.1 eq) was added to the reaction mixture and stirring was continued for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (YMC C-18 column, 30 min. gradient 25-90% aq. MeOH with 0.1% TFA). The appropriate fractions were concentrated in vacuo and the residue treated with anhydrous HCl (4 N in dioxane) at 0° C. The solution was concentrated in vacuo and the later procedure repeated three times. The residue was triturated with Et2O, discarding the filtrate and the solid was dried in vacuo to afford the title compound (0.003 g, 17%) as a white solid. 1H NMR (CD3OD) δ 7.85-7.87 (m, 2H), 7.56-7.63 (m, 3H), 7.24-7.46 (m, 6H), 7.03-7.09 (m, 3H), 6.94 (br m, 1H); MS(ESI+) m/z 440 (M+H)+, calc: 440.1523, found: 440.1517.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[Br:14][CH2:15][CH2:16]Br>O>[Br:14][CH2:15][CH2:16][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=1
Reactant: BrCCBr
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1cccc(OCCBr)c1
Reaction time: 7 h

Procedure:
A solution of NaOH at 33% (17 cc) is added dropwise to a solution of 3-trifluoromethylphenol (2.5) and 1,2-dibromoethane (30.0 g) in deionized water (30 cc). The resulting mixture is kept under refluxing conditions for 7 hours. The reaction mixture is then cooled, the oil formed is separated from the aqueous phase and distilled under a pressure of 15 mm Hg. The fraction within the range of from 118° to ° C. is collected. 26 g of the desired product is obtained.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH:45]1[CH2:50][CH2:49][CH2:48][C@@H:47]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:46]1>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([C:21]([N:45]2[CH2:50][CH2:49][CH2:48][C@@H:47]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:57])[CH3:56])[CH2:46]2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
4-Nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (Example 6A; 100 mg, 0.16 mmol) was dissolved in acetonitrile (1.25 ml), and tert-butyl (3R)-piperidin-3-ylcarbamate (96.1 mg, 0.48 mmol) was added with stirring. The mixture was stirred at RT overnight. The reaction mixture was then purified directly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm; mobile phase A: water with 0.01% formic acid, mobile phase B: acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90% B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254 nm). The product fractions were combined and concentrated under reduced pressure. This gave 81 mg (74% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:16])=O)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:58]([Si:62]([CH3:73])([CH3:72])[O:63][C:64]1[CH:65]=[C:66]([CH:69]=[CH:70][CH:71]=1)[CH2:67][NH2:68])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:16])[NH:68][CH2:67][C:66]2[CH:69]=[CH:70][CH:71]=[C:64]([O:63][Si:62]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:72])[CH3:73])[CH:65]=2)=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.2 %

Procedure:
To a solution of 3-Trifluoromethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (560 mg, 2.20 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.92 mL, 6.6 mmol), HBTU (1.0 g, 2.64 mmol), HOBT (360 mg, 2.64 mmol), and 3-(tert-Butyl-dimethyl-silanyloxy)-benzylamine (630 mg, 2.64 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-40% EtOAc in hexane to afford the desired product (0.21 g, 20% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8](C(S)C(O)=O)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[NH:17]([C:19]([O:21][CH3:22])=[O:20])[NH2:18]>O>[C:1]1([CH2:7][C:8]([NH:18][NH:17][C:19]([O:21][CH3:22])=[O:20])=[S:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(S)C(=S)Cc1ccccc1
Reactant: COC(=O)NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NNC(=S)Cc1ccccc1
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 86.0 g of 2-(2-phenyl-1-thioxoethyl)thioglycolic acid, 195 ml of 2N sodium hydroxide and 100 ml of water was added dropwise to a suspension of 50 g of methyl hydrazinocarboxylate in 200 ml of water with vigorous stirring. Stirring was continued overnight, then the mixture was extracted twice with ether. The extracts were combined, washed successively with 5% aqueous sodium bicarbonate (twice), water and saturated aqueous sodium chloride, dried and concentrated in vacuo. The dark orange oil was purified by percolation through a bed of hydrous magnesium silicate with dichloromethane. The resulting pale yellow oil was chromatographed on a 70×850 mm dry column of silica gel, eluting with dichloromethane. The resulting oil was crystallized from toluene-hexane, giving 42.6 g of the desired compound as yellow crystals, mp 93.5-94° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 3.79 (s, 3H, OCH3); 4.11 (s, 2H, CH3CS); 7.33 (bs, 5H, C6H5); 8.65 (bs, 1H, NH); 9.55 (bs, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)NCc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CS(=O)(=O)NCc1cccc(Nc2cc(-c3ccccc3OCc3ccccc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
219 mg N-[3-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide (prepared in Example 1) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 228 mg 2-benzyloxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water was added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (127 mg, 40% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][CH2:15][C:16](=[O:19])[CH2:17]I.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](=[O:27])[NH:25][CH:26]=1>>[Cl:14][CH2:15][C:16](=[O:19])[CH2:17][O:27][C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=1
Reactant: O=c1ccc(Cl)c[nH]1
Reactant: O=C(CCl)CI
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(CCl)COc1ccc(Cl)cn1

Procedure:
A protected ketone derivative wherein R2 is a 5-chloro-2-pyridyl radical, for use as a starting material in the process of the invention, may be obtained by reacting epichlorhydrin with hydriodic acid and sodium iodide to give 1-chloro-3-iodopropan-2-ol, which is oxidised by Jones' reagent to the ketone, 1-chloro-3-iodopropan-2-one. The ketone is reacted with 5-chloropyrid-2-one to give 1-chloro-3-(5-chloropyrid-2-yloxy)propan-2-one, which is converted to the protected ketone derivative, ClCH2.CR3.CH2OR2 wherein R2 is a 5-chloro-2-pyridyl radical, which in turn is reacted with a trialkyl phosphite to give the required protected ketone starting material, (R1O)2.PO.CH2.CR3.CH2OR2.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:12][C@@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:26]=3[CH:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1COCC1.N1C=CC=CC=1.N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][C:33](=[O:40])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:26]=3[CH:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 30 h
Yield: 31 %

Procedure:
To a solution of N-{7-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide (1.06 g, 1.82 mmol) in 18 mL THF/pyridine (1:1) was added approximately 20 drops of hydrofluoridic acid in pyridine. The mixture was stirred at r.t. for 30 h. The reaction was quenched by slowly adding to saturated aq NaHCO3 (100 mL) and the solution was extracted with EtOAc (3×50 mL). The combined organics were washed with saturated aq Cu(SO4)2 (50 mL) and saturated aq EDTA.Na2. The combined organics were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (15 to 50% EtOAc/hexanes) to isolate the title compound as a white foam (0.264 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C@H:24]([NH:34][CH3:35])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C@H:24]([N:34]([CH3:35])[C:10](=[O:11])[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)([CH3:14])[CH3:13])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C(=O)Cl)c1cc(Cl)cc(Cl)c1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1N(C)C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2005002577) (127 mg, 0.50 mmol) in CH2Cl2 (5 ml) was added drop wise to a stirred solution of ((3S,4R)-1-benzyl-4-o-tolyl-pyrrolidin-3-yl)-methyl-amine (the preparation of which is described herein above) (135 mg, 0.48 mmol) and ethyl-diisopropyl-amine (0.12 ml, 0.72 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 2 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:3) yielded 0.18 g (75%) of the title product as colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[CH:28]=3)[CH:20]=2)[C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[K].[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][B-](F)(F)F)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCCC1>[C:1]([C:5]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([O:15][CH3:16])=[C:7]([NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH:20]=2)[O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH2:49][N:46]3[CH2:47][CH2:48][N:43]([C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH2:44][CH2:45]3)[CH:28]=2)=[O:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(Oc3ccnc(Cl)c3)c2)c1OC
Reactant: CC(C)(C)OC(=O)N1CCN(C[B-](F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(Oc3ccnc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 414 mg methyl 5-tert-butyl-3-[3-(2-chloro-pyridin-4-yloxy)-4-methyl-benzoylamino]-2-methoxy-benzoate, 370 mg potassium-(4-tert-butyloxycarbonyl-piperazin-1-ylmethyl)-trifluoroborate, 0.84 g Cs2CO3, 0.80 ml of water and 8 ml of tetrahydrofuran is flushed for 10 min with argon. Then 200 mg of 2-dicyclohexylphosphinyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (XPhos) and 20 mg palladium(II)acetate are added, and the mixture is heated to 80° C. The reaction mixture is stirred overnight at 80° C. in an argon atmosphere. After cooling to ambient temperature the mixture is evaporated down and the residue is taken up in ethyl acetate and water. The organic phase is separated off, washed with water and aqueous saturated saline solution and dried (MgSO4). The solvent is removed, and the residue is chromatographed on silica gel with dichloromethane/methanol (99:1→90:10) and then chromatographed by reversed phase (HPLC, Xbridge C18) with methanol/water/ammonia.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.Cl[CH2:15][CH:16]=O.O.C([O-])(O)=O.[Na+]>CCO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:15]=[CH:16][N:13]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc(N)nn2)cn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2ccc3nccn3n2)cn1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
6-(1-Methyl-1H-pyrazol-4-yl)-pyridazin-3-ylamine (Stage 8.3, 2.41 g, 13.8 mmol) was dissolved in EtOH (18 mL). Chloroacetaldehyde 55% in H2O (1.61 mL, 13.8 mmol) and NaHCO3 (2.3 g, 27.5 mmol) were added. The RM was stirred at 80° C. for 5 h. The solvent was removed and a solution of 5% NaHCO3 was added. The mixture was extracted twice with DCM/MeOH (9/1). The combined organic phases were washed with brine, dried over Na2SO4, and the solvent was removed to afford the title compound as a black solid (tR 1.0 min (conditions 2), MH+=200).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]([CH2:3][CH2:4][C:5]1[CH:9]([CH:10]([CH3:11])[CH3:12])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2]
Reactant: C=C(C)C1CCC(C)=C1CCC=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1=C(CCC=O)C(C(C)C)CC1

Procedure:
3.6 g of 2-(2-formylethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene were hydrogented in 80 ml of ethyl acetate in the presence of 500 mg of palladium on calcium carbonate (5%). After the uptake of one equivalent of hydrogen, the solution was filtered over Celite, concentrated and subjected under a high vacuum to a short-path distillation. 2-(2-Formylethyl)-3-isopropyl-1-methyl-cyclopent-1-ene having a fresh, woody fragrance was obtained in quantitative yield; boiling point 0.001 about 70° C; nD20 = 1.4703; IRfilm : νmax = 2740, 1728, 1470, 1385, 1368 and 1100 cm-1.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=S)[NH:8]C3C=CC=CC=3S[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[C:22]([NH2:27])[CH:21]=1.FC1C=CC=CC=1C#N>CN(C=O)C>[F:29][C:19]([F:18])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([S:26][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=2[C:7]#[N:8])=[C:22]([NH2:27])[CH:21]=1
Reactant: S=C1Nc2ccccc2Sc2ccccc21
Reactant: Nc1cc(C(F)(F)F)ccc1S
Agent: Cl
Agent: N#Cc1ccccc1F
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Sc1ccc(C(F)(F)F)cc1N

Procedure:
Using a procedure analagous to that of Example 3(a) and (b), 4-trifluoromethyl-2-aminothiophenol hydrochloride (11.48 g, 50 mmol) was combined with 2-fluorobenzonitrile in DMF solvent (100 ml) to give crude 2-(4-trifluoromethyl-2-aminophenylthio) benzonitrile (6.84 g). Hydrolysis and subsequent condensation gave the title compound as off-white crystals from ethanol (1.1 g, m.p. 233°-235° C., Rf 0.21, CH2Cl2 /MeOH 50:1).
Reaction SMILES: B([O-])O[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C=CCCCCCC.B1C2CCCC1CCC2.[OH-].[Na+].Br[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C:37](=[O:42])[CH2:36][CH2:35]2>C1COCC1>[CH2:3]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C:37](=[O:42])[CH2:36][CH2:35]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: CCCCCCCCOB[O-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C=CCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
An octyl boronate intermediate is first generated by adding 1-octene (1.38 g, 14.1 mmol) to a solution of 9-BBN in THF (28.3 mL of a 0.5 M solution, 14.1 mmol). The reaction is stirred at room temperature overnight, then an aqueous solution of sodium hydroxide (5.0 mL of a 3.0 M solution) is added, followed by the addition of 6-bromo-2-tetralone (2.40 g, 10.0 mmol) and Pd[P(Ph)3]4 (0.310 g, 0.270 mmol). The reaction is brought to reflux and maintained for 12 hours under an inert atmosphere. The reaction is then cooled, filtered, concentrated in vacuo and the residue purified using silica gel chromatography with hexanes/ethyl acetate (75:25) as solvent to provide 6-octyl-2-tetralone (2.35 g, 8.5 mmol, 85%) as a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6](O)=[O:7].[CH3:15][NH:16][CH3:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([N:16]([CH3:17])[CH3:15])=[O:7]
Reactant: CNC
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)C)cc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
3-Methoxy-5-nitrobenzoic acid (1 g; 5.1 mmol; 1 eq) is preactivated with n-(3-dimethyl aminopropyl)-n′-ethylcarbodiimide hydrochloride (1.2 g; 6.1 mmol; 1.2 eq) in DCM (30 mL) for 10 mM. Dimethylamine (343 mg; 7.6 mmol; 1.5 eq) is then added and the reaction mixture stirred overnight. After quenching the reaction mixture with water, the organic phase is washed with water and citric acid (5%) and dried over MgSO4. The solvent is evaporated to dryness according 1.1 g (97%) of the title compound as a red oil. 1H NMR (DMSO-d5) δ 7.83-7.77 (m, 1H), 7.74-7.68 (m, 1H), 7.27-7.21 (m, 1H), 3.87 (s, 3H), 3.08 (s, 3H), 2.96 (s, 3H). HPLC (max plot) 91.9%; Rt 2.52 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[CH2:11]=[CH:12][CH:13]=[CH2:14]>>[CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]2[CH:6]([C:7](=[O:9])[CH:8]=1)[CH2:14][CH:13]=[CH:12][CH2:11]2
Reactant: COC1=CC(=O)C=CC1=O
Reactant: C=CC=C
Product: COC1=CC(=O)C2CC=CCC2C1=O

Procedure:
Little is known, however, concerning the reaction of methoxy and 2,6-dimethoxy-p-benzoquinone. (The latter can be generated from lignin). It has been shown that methoxy-p-benzoquinone will react with 1,3-butadiene to give 2-methoxy-4a,5,8,8a-tetrahydronapthoquinone [G. I. Birnbaum, J. Org. Chem., 25, 1660-1, (1960)]and with 2,3-dimethyl-1,3-butadiene to give 5,8-dihydro-2-methoxy-6,7-dimethyl -1,4-napthoquinone [M. F. Ansell, J. Chem. Soc., 3020, (1963)]. A more recent publication has shown that 2,6-dimethoxy-p-benzoquinone can be combined with isoprene to give a mixture of 2-methoxy-6-methyl-1,4-napthoquinone and 2-methoxy-7-methyl-1,4-napthoquinone [I.-M. TegmoLarsson, Tetra. Letters, 22, 2043-6, (1981)].
Reaction SMILES: Cl.[CH:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:18])([C:15]([OH:17])=[O:16])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:7]=1.[CH2:19]([O:21]CC)[CH3:20]>>[C:19]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:18])[C:15]([OH:17])=[O:16])(=[O:21])[CH3:20]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: Cl
Product: CC(=O)c1ccccc1C(O)(C(=O)O)c1ccccc1

Procedure:
Acetyl chloride (35 mL, 490 mmol) was added dropwise to a solution of benzilic acid (100 g, 438 mmol) in 300 mL THF over a period of five minutes. The solution was cooled to 0° C. and pyridine (70 mL, 865 mmol) was added dropwise over a period of 30 minutes, during which time a thick white precipitate developed. The ice bath was removed, the reaction flask was equipped with a CaCl2 drying tube and stirred overnight. The next day, the solution was filtered to isolate a white precipitate and the yellow THF supernatant was concentrated to a turbid oil. Most of the product was isolated in the precipitate as the pyridinium acetylbenzilate salt, but some was retained in the supernatant. The precipitate and oil were added to a large separatory funnel charged with 1000 mL diethyl ether and 400 mL of 1.2M HCl. The contents were thoroughly mixed, the aqueous portion separated and discarded. The ether solution was washed twice with 400 mL 1.2M HCl, once with 300 mL saturated NaCl solution, dried over MgSO4, filtered and concentrated to approximately 200 mL. The product was precipitated by addition of 800 mL hexanes, isolated by filtration, and air dried overnight. Yield 88 g (74%). 1H NMR (CDCl3): δ7.1-7.7 (m, 10H ArH), 5.7 (s, 3H, COOH), 2.08 (s, 3H, RO(O)CCH3). This synthesis could be easily modified by one of skill in the art to incorporate a thiol or amino analog of benzylic acid.