Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[Sn](CCCC)(CCCC)CCCC.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][C:14]1[C:13]([O:12][CH2:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:26]2[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=2)[N:7]=3)=[CH:21][CH:20]=[C:19]([F:22])[C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cccc1-c1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.10 g, 0.24 mmol) in 5 ml of anhydrous DMF was added 1-methyl-2-tributylstannanyl-1H-pyrrole (0.120 g, 0.32 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.004 g, 0.0037 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. The reaction mixture was then cooled to room temperature, added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/Hexane (40:60) as the eluent to provide the title compound as yellow solid (0.032 g, 32%). 1H NMR (DMSO-d6, 400 MHz): δ 3.73 (s, 3H), 5.72 (s, 2H), 6.13 (br s, 1H), 6.40 (br s, 1H), 6.97 (s, 1H), 7.12 (m, 1H), 7.42 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H), 8.48 (s, 1H) and 8.75 (s, 1H). MS ES+ (401.26), HPLC (method I) Rt=15.61 min.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[CH3:12][O:13][C:14](=[O:18])[C:15]#[C:16][CH3:17].CCN(CC)CC>CCOCC>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:16]=1[CH3:17])=[O:18]
Reactant: CC#CC(=O)OC
Reactant: ON=C(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1c(-c2ccccc2F)noc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.2 %

Procedure:
To a solution (0° C., N2) of 2-fluorobenzoylchloride oxime (0.50 g, 2.9 mmol) and methyl-2-butynoate (0.57 g, 5.8 mmol) in Et2O (15 ml) was added a solution of Et3N (0.52 ml) in Et2O (2 ml) over a period of 1 h followed by warming to room temperature while stirring overnight (17 h). The reaction was diluted with Et2O, washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, hexanes/EtOAc gradient) gave the title compound (0.39 g, 58%).
Reaction SMILES: ClC[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].[SH:12][C:13]1[N:21]=[CH:20][N:19]=[C:18]2[C:14]=1[NH:15][CH:16]=[N:17]2.[CH:22](Cl)(Cl)Cl>>[C:5]([NH:7][CH2:22][S:12][C:13]1[N:21]=[CH:20][N:19]=[C:18]2[C:14]=1[NH:15][CH:16]=[N:17]2)(=[O:6])[C:4]1[CH:3]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1ncnc2nc[nH]c12
Reactant: NC(=O)c1ccccc1CCl
Reactant: ClC(Cl)Cl
Product: O=C(NCSc1ncnc2nc[nH]c12)c1ccccc1

Procedure:
Chloromethylbenzamide (55.71 mg, 0.328 mmol) and 6-mercaptopurine (50 mg, 0.328 mmol) were dissolved in 1.5 ml of dry DMSO-d6 to give a clear yellow solution. The progress of the reaction was followed by monitoring changes in the NMR spectrum. The doublet at 5.42, due to chloromethylbenzamide, had completely disappeared after 10 hours and a new doublet at 5.83 indicated the presence of the benzamidomethylthio moiety. Chloroform was added which caused a yellow gum to precipitate which was washed several times with chloroform and crystallized from methanol: mp 197°-200° C.; IR (KBR) 1720 cm-1 ; NMR (pyridin-d5) δ8.39-7.35 (m, 5, aryl), 5.99 (d, 2, --SCH2NH--); MS m/e 285 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[S:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[S:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1OC

Procedure:
Prepared as in example 5-10 from (3,4-dimethoxyphenyl)methanamine, methyl 4-(chlorosulfonyl)benzoate (Example 5-10c) and benzyl chloride. MS (M−H, 440.10); 1H NMR (400 MHz, CD3OD): δ, ppm: 3.59 (s, 3H), 3.76 (s, 3H), 4.30 (s, 2H), 4.36 (s, 2H), 6.51 (d, 1H, J=1.7 Hz), 6.60 (m, 1H), 6.76 (d, 1H, J=8.2 Hz), 7.12 (m, 2H), 7.21 (m, 3H), 7.95 (d, 2H, J=8.6 Hz), 8.18 (d, 2H, J=8.6 Hz).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[C:30]1([C:40](=[O:42])[CH3:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1>ClCCl>[C:30]1([C:40]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)([OH:42])[CH3:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)c1nccc2ccccc12
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1nccc2ccccc12
Reaction time: 16 h

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available) (15.5 g, 35.4 mmol) in dichloromethane (80 mL) at 20° C. was treated with ethyl magnesium bromide (12.0 mL, 36 mmol, 3M in ether) and allowed to react for 1 h. A solution of 1-isoquinolin-1-yl-ethanone (Intermediate H2) (3.65 g, 21.3 mmol) in dichloromethane (20 mL) was added via addition funnel at 20° C. and stirred for 16 h. The mixture was quenched with sat. ammonium chloride (100 mL) and diluted with dichloromethane. The residue was isolated in an aqueous workup. The product was extracted with CH2Cl2 and purified by chromatography on silica gel with 5% NH3-MeOH: CH2Cl2 to give 1-isoquinolin-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate H3) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.S(Cl)([Cl:12])=O>ClCCl>[ClH:12].[Cl:12][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: Nc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: Nc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 2.0 g (16.24 mmol) of 3-aminobenzyl alcohol were initially charged in 60 ml of dichloromethane. 5.8 g (48.72 mmol) of thionyl chloride were added dropwise, and the reaction solution was stirred at RT overnight. The reaction solution was evaporated.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].IC.[CH3:18][Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1.O>[CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([C:13]#[N:14])([CH3:18])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC2CC(C)(C#N)CC2C1
Yield: 53.9 %

Procedure:
5-Cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a (4.2 g, 20.2 mmol) and iodomethane (11.5 g, 80.8 mmol) were dissolved in 100 mL of tetrahydrofuran followed by dropwise addition of lithium hexamethyldisilazide (80.8 mL, 80.8 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was reacted for 2 hours until MS showed the disappearance of the starting materials. The mixture was diluted with 100 mL of water and extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an oil. TLC showed that there are two adjacent spots, and then the oil was purified by silica gel column chromatography to obtain the bottom spot compound 5-cyano-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12b (2.411 g) as a light yellow oil.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:28]\[OH:29])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:29]/[N:28]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]\1[CH2:19][C:20](=[O:50])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2]
Reactant: C[C@]12CCCCC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 70 %

Procedure:
The title compound II-at was prepared in 70% yield from 3,3:17,17-bis(ethylendioxy)-6(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 70/30). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.61 (s, 1H), 3.29 (dd, 1H), 2.61-1.03 (m, 19H), 0.88 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:12]([CH3:14])[CH3:13])[C:6]=1[C:7](OCC)=[O:8].[CH:15]([NH2:17])=O>>[OH:8][C:7]1[C:6]2[C:5]([CH:12]([CH3:14])[CH3:13])=[CH:4][S:3][C:2]=2[N:1]=[CH:15][N:17]=1
Reactant: CCOC(=O)c1c(C(C)C)csc1N
Reactant: NC=O
Product: CC(C)c1csc2ncnc(O)c12

Procedure:
Using ethyl 2-amino-4-isopropylthiophene-3-carboxylate (800 mg, 3.8 mmol) and formamide (5 ml), a similar procedure to a) in Production Example 208 was carried out to obtain 4-hydroxy-5-isopropylthieno[2,3-d]pyrimidine (330 mg, 1.7 mmol) having the following physical properties:
Reaction SMILES: [OH-].[Na+].[C:3]([CH:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)([O:5]CC)=[O:4]>O.C(O)C>[F:27][C:23]1[CH:22]=[C:21]([CH:14]([CH2:8][C:3]([OH:5])=[O:4])[CH2:15][C:16]([OH:18])=[O:17])[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(c1cccc(F)c1)C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC(CC(=O)O)c1cccc(F)c1
Yield: 77.3 %

Procedure:
To a hot solution of sodium hydroxide (19.15 g, 0.479 mol) in water (50 mL) was added a solution of diethyl 2-carbethoxy-3-(3-fluorophenyl)glutarate (18.8 g, 0.0532 mol) in ethanol (36 ml). The resulting slurry was refluxed for 5 hrs. The mixture was poured into icewater and the ethanol was removed by spin evaporation in vacuo. The residual aqueous solution was acidified with concentrated hydrochloric acid (12 N) and the solution (200 mL) was extracted with ethyl acetate (3×300 ml). The ethyl acetate layers were combined, washed with water (50 ml) and the volatiles were removed by spin evaporation in vacuo to give a solid that was recrystallized from dichloromethane and hexanes to give 9.3 g (77%) of 3-(3-fluorophenyl)glutaric acid a white solid; m.p., 126-127.5° C.;
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([CH:9]([CH2:20][CH:21]=[CH2:22])[CH2:10][O:11][SiH2:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1)[CH:7]=[CH2:8].C(C(CC=C)[CH2:27][O:28][SiH2]C1C=CC([Mg]Cl)=CC=1)C=C.CN(C=O)C.Cl>C1COCC1>[CH2:6]([CH:9]([CH2:20][CH:21]=[CH2:22])[CH2:10][O:11][SiH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:27]=[O:28])=[CH:15][CH:14]=1)[CH:7]=[CH2:8]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc([Mg]Cl)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCC(CC=C)CO[SiH2]c1ccc(C=O)cc1
Yield: 85 %

Procedure:
Firstly, i-PrMgCl (0.71 mL, 2 M in THF, 1.42 mmol) was added dropwise to a THF solution (2 mL) of 4-(diallylethoxysilyl)iodobenzene (255 mg, 0.71 mmol) obtained in Synthesis example 7 at −30° C. The resultant mixture was stirred under a nitrogen atmosphere at −30° C. for 1.5 hours to obtain a solution containing 4-(diallylethoxysilyl)phenylmagnesium chloride (Grignard solution). Then, DMF (110 μL, 1.42 mmol) was added dropwise to the obtained solution at −30° C., and the resultant mixture was stirred under a nitrogen atmosphere at room temperature for 13 hours to obtain a reaction mixture. Subsequently, an aqueous solution of HCl of 10% by mass was added to the reaction mixture to cease the reaction. After that, an organic layer was separated from the reaction mixture, and an aqueous layer was extracted with ether. The organic layer thus collected was washed with sat. NaHCO3 and sat. NaCl, and dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=20/1) to obtain 4-(diallylethoxysilyl)benzaldehyde (158 mg, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.C1(C(Cl)=[O:32])CC1.[C:34]1([CH3:40])[CH:39]=[CH:38][CH:37]=CC=1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:40]([CH2:34][CH:39]1[CH2:38][CH2:37]1)=[O:32]
Reactant: NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Reactant: Cc1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Product: O=C(CC1CC1)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 200 g (0.667 mol) of 2-[2-chloro-4-(3,5-difluorophenoxy)phenoxy]ethylamine, 81 g (0.80 mol) of triethylamine and 8 liter of toluene, there was added dropwise a solution of 70 g (0.67 mol) of cyclopropane carbonylchloride in 2 liter of toluene with stirring at a temperature of from 5° C. to 10° C. After 2 hours, the reaction mixture was stirred at a room temperature for 15 hours. After the reaction was completed, the resultant mixture was washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 163 g of N-{2-[2-chloro-4-(3,5-difluorophenoxy)phenoxy]ethyl}-cyclopropane carboxyamide as a white crystal (m.p. 89°-90° C.).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32].C(OCC)(=O)C>CS(C)=O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:33]([C:34]([OH:36])=[O:35])[C@H:31]([OH:32])[C:30]([OH:38])=[O:37]
Reactant: O=C(O)CC(O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)C[C@H](O)C(=O)O
Reaction time: 1 h

Procedure:
1 g of sunitinib base was suspended in 4 ml of DMSO, at RT. 0.336 g of Malic acid added (as a solid) obtaining a solution, then 20 ml of ethyl acetate were added drop wise and precipitation was observed. The suspension was kept at 20-25° C. for 1 hour then filtered and washed with ethyl acetate. Dried at 80° C. under vacuum for 16-18 h affording 1.03 g of Sunitinib Malate.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10](O)[C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:10]1[C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12]
Reactant: Cc1nc2c(C)cccc2c(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(C)cccc2c(Cl)c1C

Procedure:
Prepared according to procedure S using 2,3,8-trimethylquinolin-4-ol (1.7 g, 9.1 mmol) in POCl3 (12.5 mL, 136 mmol). The resulting precipitate was collected by filtration to give 4-chloro-2,3,8-trimethylquinoline. Mass Spectrum (ESI) m/e=206 (M+1).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[K+].[Br-]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:23][CH2:24]2)=[O:3])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: c1ccc(CCCCN2CCNCC2)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Cl)cc1)N1CCN(CCCCc2ccccc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-chlorophenyl chloroformate and 1-(4-phenylbutyl)piperazine, yield 86%. White crystals, m.p. 230-232° C.; 1H NMR (DMSO-d6): δ11.43 (br, 1H), 7.51-7.43 (d-like m, 2H), 7.33-7.15 (m, 7H), 4.33-3.95 (br, max at 4.21 and 4.10 ppm; 2H), 3.72-3.36 (br m, 4H), 3.22-2.96 (br, max at 3.10 ppm, 4H), 2.62 (t, J=7.54 Hz, 2H), 1.84-1.69 (m, 2H), 1.69-1.54 (m, 2H) ppm; IR (KBr): ν 1736, 1720 (C═O) cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Nc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ccccc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
Combine 4-bromophenylboronic acid (6.064 g, 30.195 mmol), 2-iodo-phenylamine (5.532 g, 25.257 mmol), toluene, 2N Na2CO3 (13 ml, 26 mmol), and tetrakis(triphenyl-phosphine)palladium(0) (0.849 g) and heat to 80° C. After 4 hours cool to room temperature and stir for 16 hours. Dilute the reaction with EtOAc and back extract water layer with EtOAc. Combine the organic layers and wash with H2O, and dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography (silica gel), eluting with first hexane and increasing up to 10% EtOAc/Hexane to afford 4′-bromo-biphenyl-2-ylamine (4.008 g, 64%). LCMS 247.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:23]([CH3:24])[C:22](=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1>CS(C)=O>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:23]([CH3:24])[C:22](=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)n(C)c(=O)c2c1
Reactant: ClCCCCBr
Solvent: CS(C)=O
Product: COc1ccc2nc(-c3ccc(OCCCCCl)cc3)n(C)c(=O)c2c1
Temperature: 25 °C

Procedure:
4 gm (0.014 mol) of the product in (b) were dissolved in 30 ml of dimethylsulfoxide, and the solution was mixed, while stirring, with 1.75 gm (0.014 mol+10%) of potassium tert. butylate. Subsequently, 4 ml of 1-bromo-4-chlorobutane were added, and the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was poured into ice water, and the crystalline precipitate thus formed was suction-filtered off, washed well with water and dried.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[H][H].O1C2C(=CC=CC=2)C=CC1=O>O1CCOCC1.[Pd]>[C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)OCc3ccccc3)cc2cc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: O=c1ccc2ccccc2o1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)O)cc2cc1Cl

Procedure:
7-Butyryloxy-3-carboxymethylaminocarbonyl-6-chlorocoumarin was prepared as follows. 920 mg (2 mmol) 7-butyryloxy-3-benzyloxycarbonylmethylaminocarbonyl-6-chlorocoumarin were dissolved in 50 ml dioxane. 100 mg palladium on carbon (10%) and 100 microliters acetic acid were added to the solution and the suspension stirred vigorously in a hydrogen atmosphere at ambient pressure. After the uptake of hydrogen seized the suspension was filtered. The product containing carbon was extracted five times with 25 ml boiling dioxane. The combined dioxane solutions were let to cool upon which the product precipitated as a white powder. Reduction of the solvent to 20 ml precipitates more product. The remaining dioxane solution is heated to boiling and heptane is added until the solution becomes cloudy. The weights of the dried powders were 245 mg, 389 mg and 58 mg, totaling 692 mg (1.88 mMol, 94%) of white product. 1H NMR (dDMSO): δ 1.02 ppm (t, 3H, J=7.4 Hz, butyric methyl), δ 1.73 ppm (m, 2H, J1≈J2=7.3 Hz, butyric methylene), δ 2.70 ppm (t, 2H, J=7.2 Hz, butyric methylene), δ 4.07 ppm (d, 2H, J=5.6 Hz, glycine methylene), δ 7.67 ppm (s, 1H, coumarin), δ 8.35 ppm (s, 1H, coumarin), δ 8.90 ppm (s, 1H, coumarin), δ 9.00 ppm (t, 1H, J=5.6 Hz, amide).
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].[CH:19](=O)[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>>[O:24]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:19]1[O:12][C:3]([C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:1][O:2]1
Reactant: O=Cc1ccco1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Product: O=C(c1ccccc1)C1(c2ccccc2)COC(c2ccco2)O1
Yield: 78 %

Procedure:
The procedure of Example 1 was repeated except that the starting materials were α-methylolbenzoin and furfural. The product, 2-furyl-4-benzoyl-4-phenyl-1, 3-dioxolane, was obtained in a yield of 78% and analyzed as follows:
Reaction SMILES: CS(Cl)(=O)=O.O[C:7]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][O:10][C:9]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:8]1=2.C(N(CC)CC)C.O>ClCCl>[O:17]=[C:16]1[C:8]2[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][O:10][C:9]=2[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCOC(=O)C1(O)COC2=C1C(=O)CCCC2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1coc2c1C(=O)CCCC2
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (9.7 g, 0.08 mol) was added dropwise to a stirring solution of ethyl 3-hydroxy-4-oxo-2,3,5,6,7,8-hexahydro-4H-cyclohepta[b]furan-3-carboxylate (17 g, 0.07 mol) and triethylamine (30 mL, 0.21 mol) in dichloromethane (100 mL) at 0° C. The mixture was allowed to reach ambient temperature, stirred for 2 hours, then poured into water and extracted with dichloromethane. The organic layer was washed sequentially with aqueous 2N sodium hydroxide, saturated aqueous sodium bicarbonate, and brine, then dried over magnesium sulfate, filtered, concentrated in vacuo, and purified on Silica gel (1:1 ethyl acetate/hexanes) to give the title compound.