Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C(F)=C([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])N=C(C(OC(C)C)=O)C=1.[C:25]([NH:28][C:29]1[C:34]([F:35])=[C:33](Br)[N:32]=[C:31]([C:37]([O:39][CH3:40])=[O:38])[CH:30]=1)(=[O:27])[CH3:26]>>[C:25]([NH:28][C:29]1[C:34]([F:35])=[C:33]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:32]=[C:31]([C:37]([O:39][CH3:40])=[O:38])[CH:30]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)c1cc(NC(C)=O)c(F)c(Br)n1
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Product: COC(=O)c1cc(NC(C)=O)c(F)c(-c2ccc(Cl)c(OC)c2F)n1

Procedure:
Methyl 4-(acetylamino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate was prepared in analogous fashion to isopropyl 4-(amino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate in Example 10 except that methyl 4-acetamido-6-bromo-5-fluoropicolinate was used in place of isopropyl 4-amino-6-bromo-5-fluoropicolinate: mp=189-191° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H), 9.04 (d, JF-H=5.6 Hz, 1H), 7.53 (dd, J=8.4, 1.6 Hz, 1H), 7.37 (dd, J=8.4, 7.0 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.22 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 170.3, 164.1, 154.4, 151.9, 149.4, 146.7, 144.1-143.8 (m), 140.5 (d, JF-C=15.3 Hz), 135.1 (d, JF-C=10.8 Hz), 128.9 (d, JF-C=3.4 Hz), 125.9 (dd, JF-C=35.0, 3.5 Hz), 122.9 (dd, JF-C=13.7, 3.5 Hz), 61.6, 52.6, 24.1; 19F {1H} NMR (376.5 MHz, DMSO-d6) δ −129.5 (d, JF-F=27.5 Hz), −142.8 (d, JF-F=27.5 Hz); IR: 3341, 2972, 2944, 1733, 1705, 1599, 1507, 1439, 1416, 1406, 1371, 1283, 1166, 1039, 974, 926, 890, 823, 678; MS Calcd. for C16H13ClF2N2O4: 370.1. Found: 370 (M+), 312.
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>O1CCCC1>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 40.4 %

Procedure:
A solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.110 g, 4.299 mmol) in tetrahydrofuran (17 ml) was added with lithium hydroxide monohydrate (0.171 g, 4.08 mmol), and the mixture was stirred for approximately 1.2 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.962 g, 2.41 mmol) in tetrahydrofuran (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, the solution was concentrated under reduced pressure. Ethyl acetate and water were added to the residue and stirred, then, the mixture was let to stand and separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 38 g; ethyl acetate:hexane=1:4), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.517 g; 0.973 mmol; yield: 40.4%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:14])[CH:10]=[C:11](O)[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C[O:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[NH2:36]>C(O)CCCCC>[OH:14][C:9]1[C:10]2[C:29](=[O:28])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][C:31]=3[NH:36][C:11]=2[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:8]=1
Reactant: Oc1cc(O)cc(N2CCOCC2)c1
Reactant: COC(=O)c1cccnc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCO
Solvent: O
Product: O=c1c2cccnc2[nH]c2cc(N3CCOCC3)cc(O)c12
Yield: 2.1 %

Procedure:
5-Morpholin-4-yl-benzene-1,3-diol (345 mg 1.77 mmol), TsOH.H2O (30 mg, 0.20 mmol), and 2-aminonicotinic acid methyl ester (269 mg, 1.77 mmol) were heated at 160° C. in hexanol (5 mL) for 12 hours. Upon cooling, the mixture was purified via flash chromatography CH2Cl2/MeOH (95:5), followed by a second flash column eluting with Et2OAc/hexanes (7:3) to provide 11 mg (2%) of the product. 1H NMR (CDCl3, 400 MHz) δ: 13.5 (s, 1H), 8.80 (br s, 1H), 8.62 (d, 1H), 7.25 (dd, 1H), 6.22 (d, 1H), 6.04 (s, 1H), 5:97 (s, 1H), 3.86-3.83 (m, 4H), 3.40-3.35 (m, 4H). LRMS (APCI, positive): Da/e 296.4 (m−1).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C1COCC1.[CH2:10]([N:12]([CH2:24][CH3:25])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[CH:21]([CH3:23])[CH3:22])[CH3:11]>>[CH2:24]([N:12]([CH2:10][CH3:11])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]([OH:18])[C:1]#[CH:2])=[CH:15][C:14]=1[CH:21]([CH3:23])[CH3:22])[CH3:25]
Reactant: CCN(CC)c1ccc(C=O)cc1C(C)C
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(N(CC)CC)c(C(C)C)c1
Yield: 83.8 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 9.3 ml (4.7 mmol) of 0.5M ethynylmagnesium bromide/THF with 780 mg (3.5 mmol) of 4-diethylamino-3-isopropylbenzaldehyde. 720 mg of 1-(4-diethylamino-3-isopropylphenyl)prop-2-yn-1-ol are obtained in the form of a yellow oil (yield=83%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5].CC(C[AlH]CC(C)C)C>O1CCCC1.CCCCCCC>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:6]([CH:4]=[O:5])[N:7]=1
Reactant: CON(C)C(=O)c1cc2ccccc2cn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.35 g (6.24 mmol) of isoquinoline-3-carboxylic acid methoxy-methyl-amide was dissolved in 50 ml tetrahydrofuran, 7.49 mL of 1.0 M DIBAL solution in heptane was added at −78° C. The reaction was warmed to room temperature and stirred for 1 hour at r.t., and then quenched by addition of 10 mL saturated sodium bicarbonate. 100 mL of water was added followed by extraction with 100 ml of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuum to give colorless oil. The crude was used to next step without further purification. LC-MSD, m/z for C10H7NO [M+H]+: 158.2. LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 min: 0.221 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21]Br>CN(C=O)C.C(OCC)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:21][CH2:20][NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)NCCO2
Temperature: 70 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
To a 2000 ml three-necked flask under N2 containing 3-Amino-4-hydroxy-benzoic acid methyl ester (31.35 g, 187 mmol) in anhydrous DMF (630 ml; 20 vols) at RT, was added K2CO3 (103 g, 4 eq.) in one portion followed by 1,2dibromoethane (65 ml, 4 eq.) in one portion. The reaction mixture was stirred at 70° C. for 12 h. Temperature was allowed to cool down to RT, and HCl1N was added until pH=8, and extraction was performed using diethyl ether (3*200 ml). The organic phase was washed with water (2*200 ml) and dried over MgSO4 and concentrated to afford a brown red oil with solid, which was taken up again in diethyl ether (450 ml) and THF (50 ml) and filtered to remove a white solid. To the filtrate was added HCl1N, and diethyl ether (130 ml) was added, suspension was stirred at RT for 5 minutes and filtered to give 27.6 g of crude product. The aqueous phases were again extracted with ethyl acetate to afford additional 6.23 g of product. The combined fractions (32 g) were recrystallised from EtOH (420 ml; 13 vols) to give after filtration and drying a white powder (19.47 g (16.37 g free base)), yield=40%.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[NH2:10][C:11]1[CH:12]=[C:13]([C:21]([O:23]C)=O)[CH:14]=[C:15]([C:17]([O:19]C)=O)[CH:16]=1.O>C(Cl)Cl>[N:5]1([C:21]([C:13]2[CH:12]=[C:11]([CH:16]=[C:15]([C:17]([N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[O:19])[CH:14]=2)[NH2:10])=[O:23])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: C[Al](C)C
Solvent: O
Solvent: ClCCl
Product: Nc1cc(C(=O)N2CCCC2)cc(C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of AlMe3 (2M in toluene, 19.5 mL, 2 eq) was added dropwise to a solution of pyrrolidine (3.25 mL, 2 eq) in 50 mL of anhydrous DCM at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. 1,3-Dimethyl 5-aminobenzene-1,3-dicarboxylate (4.10 g, 19.5 mmol) was added and the reaction mixture was refluxed for 38 h. The mixture was then poured in ice cooled water and filtered. The aqueous filtrate was extracted with CHCl3. The combined organic layers were dried over MgSO4, filtered and evaporated to give 3.5 g of expected compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl[SiH:9]([CH3:11])[CH3:10].C(N(CC)CC)C>CCCCCCC>[CH2:1]([N:4]([SiH:9]([CH3:11])[CH3:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C[SiH](C)Cl
Reactant: C=CCNCC=C
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: C=CCN(CC=C)[SiH](C)C

Procedure:
The preparation of azasilacyclobutanes can be illustrated by the following: Diallylamine was reacted with chlorodimethylsilane in heptane in the presence of triethylamine to give diallylaminodimethylsilane as shown by the following equation ##STR13## The silane product was obtained by ambient pressure distillation after removal of triethylamine hydrochloride by filtration. 1-allyl-2,2,3-trimethyl-1-aza-2-silacyclobutane was made by intramolecular hydrosilation of the diallyldimethylsilane. This reaction was carried out at 80° C. in the presence of PtCl2 (PPh3)2 in benzene. The starting material was consumed in four hours to give a product mixture of 83 mole percent of the azasilacyclobutane and 17 mole percent of azasilacyclopentane as illustrated by the following equation ##STR14## Total yield of product was 77 weight percent. The azasilacyclobutane can be reacted with 1,1,3,3-tetramethyldisiloxane in the presence of a platinum catalyst which in turn can be reacted with an alkoxysilane having aliphatic unsaturation as described above to make an azasilacyclobutyl functional alkoxysilane of Formula (A).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.Cl.[N:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.O1CCOCC1>[N:20]([C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=3[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)=[CH:25][CH:24]=1)=[N+:21]=[N-:22]
Reactant: CCOc1ccc(I)cc1-c1cc(Cl)nc(N)n1
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: CCOc1ccc(I)cc1-c1cc(Nc2ccc(N=[N+]=[N-])cc2)nc(N)n1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
To a mixture of 4-chloro-6-(5-iodo-2-ethoxy-phenyl)pyrimidin-2-ylamine (7.0 mg, 0.02 mmol) and 4-azidoaniline hydrochloride (5.0 mg, 0.03 mmol) in tert-butanol (1 ml) was added a 1 M hydrogen chloride in dioxane (0.2 ml). The mixture was heated at 90° C. for 2 hours. After cooling to room temperature, the mixture was treated with 1 M aqueous sodium bicarbonate solution (1 ml) and extracted with ethyl acetate (2×1 ml). The combined extracts were concentrated under reduced pressure and the residue was purified by preparative TLC eluting with 35% ethyl acetate-hexane to provide the title compound (6 mg, 68% yield) as a light brown solid. 1H NMR (CDCl3) δ 8.20 (d, J=2.3 Hz, 1H), 7.60 (dd, J=2.3, 8.70 Hz, 1H), 7.38 (d, J=8.70 Hz, 2H), 7.04 (d, J=8.70 Hz, 2H), 6.77 (s, 1H), 6.72 (d, J=5.0 Hz, 1H), 6.63 (br s, 1H), 4.91 (br s, 2H), 4.09 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.O=[C:21]([CH3:32])[CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26].C(O)(=O)C>C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:22]([C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[C:25]([OH:27])=[O:26])=[C:21]2[CH3:32])=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1C(=O)O
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(-c1ccccc1C(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 65 °C
Yield: 36 %

Procedure:
A solution of the hydrazine from Example 1, Step 5, (675 mg, 2.2 mmol), 2-(2-oxopropyl)benzoic acid (425 mg, 2.4 mmol) and acetic acid (314 μL, 5.5 mmol) in toluene was warmed to 65° C. for 1-- h after what the mixture was evaporated and acetic acid was removed with the help of heptane in vacuo. To a portion of the residue (100 mg) in dioxane (1 mL) was added 4M HCl in dioxane (2 mL) and the mixture was heated to 65° C. for 1 h. It was then cooled to 25° C. and poured on a mixture of ice water and ethyl acetate. The organic layer was washed with brine and dried with MgSO4. Removal of the solvents yielded a residue which was purified by flash chromatography. The remaining portion of the intermediate was processed identically and combined to give the product (357 mg). Anal. Calcd. for C24H20BrNO3 : C, 64.01; H, 4.48; N, 3.11. Found: C, 63.92; H, 4.51; N, 3.04.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:13])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(-c2ccc(Br)s2)cc1
Product: O=C(c1ccc(-c2ccc(Br)s2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D using 4-(5-Bromo-thiophen-2-yl)-benzoic acid (CAS 1545208-54-4) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine to give the title compound (5.42 g). MS (ES+) 419.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=N[CH2:38][CH2:39][CH2:40][N:41](C)C)C.ON1C2C=CC=CC=2N=N1.C1(N)CC1>O.CN(C)C=O>[CH:40]1([NH:41][C:18](=[O:19])[CH2:17][CH:14]2[S:13][C:12]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[CH:6][C:5]([O:21][C:22]3[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=3)=[CH:4][C:3]=4[O:2][CH3:1])=[N:16][CH2:15]2)[CH2:38][CH2:39]1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC4CC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min, and then cyclopropylamine (50 mg) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate-hexane and collected by filtration to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (150 mg, 68%) as colorless prisms. MS 501 (MH+). mp 248-249° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1)(=O)=O>CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nccc2ccccc12
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CO
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nccc3ccccc23)c1
Yield: 18.2 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.04 g) and 1-methylsulphonylisoquinoline (1.70 g) were fused at 135° C. for 51/4 hours. The cooled reaction mixture was taken up in methanol, filtered, evaporated and subjected to medium pressure column chromatography on silica (chloroform:methanol 1:19 - second column using chloroform) to give the title compound (0.56 g) as an oil. This was treated with maleic acid (0.35 g) in warm ethanol to yield, on cooling, 1-[3-[3-(piperidinomethyl)phenoxy]propylamino]isoquinoline dimaleate (0.15 g), m.p. 103°-5° C. (recrystallised from ethanol).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1>C(N(CC)CC)C.C(O)=O>[CH2:2]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=c1oc2ccccc2c(O)c1Cc1ccccc1

Procedure:
Scheme 2 provides an alternative synthesis of C-3 substituted 4-hydroxycoumarins when R1 is aryl groups. 4-hydroxycoumarin and an aromatic aldehyde can be heated in a mixture of triethylamine and formic acid (2:5 molar ratio) to give 3-benzyl-4-hydroxycoumarin, which was in turn treated with 2.2 eq. of BuLi and quenched with carbon dioxide to give coumarin substituted phenyl-acetic acid. Corresponding esters can be obtained by treating the acid with various alcohols in the presence of concentrated sulfuric acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][N:17]=[C:16]([CH:19]3[CH2:21][CH2:20]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH:19]1([C:16]2[N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[O:18][N:17]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CC3)no2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC(c2nc(C3CC3)no2)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Tert-butyl-4-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylate (1.1 g, 3.8 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (4 mL) was further added thereto. The reaction mixture was stirred at room temperature for 1 hour, neutralized with sodium bicarbonate, and extracted with dichloromethane two times. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (600 mg) as yellowish and transparent oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][CH3:15])[CH2:24][CH2:25]2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (21.2 g) was added portionwise to a stirred solution of 1-(2-methoxyphenyl)piperazine (commercially available, 19.23 g) and 1-benzyl-4-piperidone (commercially available, 18.93 g) in CH2Cl2 (300 mL) at room temperature, followed by glacial acetic acid (6 mL). The resulting mixture was stirred at room temperature for 24 hours. The reaction was made basic by careful addition of saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give the desired product (20.65 g) as an off-white solid which was used without further purification. The compound was characterized as the dihydrochloride salt, which was formed by dissolving the free base in ethanol and treating it with an excess of 1 N HCl/Et2O to give a white solid, which was collected by vacuum filtration, washed with Et2O and dried in vacuo; MP. 238-242° C.; MS (ES) m/z (relative intensity) 366 (M+H)+ (100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>C(#N)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[C:10](=[O:15])[C:11]([CH3:13])([CH3:14])[O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)OC(C)(C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)OC(C)(C)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a stirred solution of 5-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (600 mg, 1.93 mol) in acetonitrile (50 mL) was added K2CO3 (800 mg, 5.8 mol). 2-Chloromethyl quinoline (500 mg, 2.32 mol) was added dropwise under an inert atmosphere. The reaction mixture was stirred at 80° C. for 16 h and then partitioned between water and EtOAc (200 mL). The organic layer was separated, washed with water, dried over Na2SO4 and then concentrated in vacuo to obtain a residue. The residue was purified via silica gel column chromatography to afford 4-(4-methoxyphenyl)-2,2-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (0.51 g, 58%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.45 (d, J=7.2 Hz, 1H), 8.02-7.97 (m, 2H), 7.85-7.77 (m, 1H), 7.76-7.68 (m, 2H), 7.59-7.51 (m, 2H), 7.19-7.11 (m, 4H), 6.95 (d, J=7.4 Hz, 2H), 5.41 (s, 2H), 3.75 (s, 3H), 1.45 (s, 6H). MS: M+H: m/z=452.1. HPLC: 97%, (Condition-I).