Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:29]1C2C=CC(C3(C(NC4C=CC(Br)=CN=4)=O)CC3)=CC=2O[CH2:30]1.[Cl-].COC1C=CC(C[Zn+])=CC=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ccc(Cc2ccccc2)cn1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: O=C(Nc1ccc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: COc1ccc(C[Zn+])cc1
Agent: [Cl-]
Product: COc1ccc(Cc2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)nc2)cc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(4-methoxybenzyl)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-benzylpyridin-2-yl)cyclopropanecarboxamide by reacting 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromopyridin-2-yl)cyclopropanecarboxamide with (4-methoxybenzyl)zinc(II) chloride.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([O:11][C:12]([NH:14][C:15]1[S:16]C(C(O)=O)=[CH:18][N:19]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>ClCCl.O1CCCC1.CN(C)C=O>[C:7]([O:11][C:12](=[O:13])[NH:14][C:15]1[S:16][C:1]([C:2]([Cl:4])=[O:3])=[CH:18][N:19]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The third step involves adding a 2M solution of oxalyl chloride in dichloromethane to a stirred solution of 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid in tetrahydrofuran and N,N-dimethylformamide, and then stirring the solution at room temperature for 4 hours. The solvent was evaporated under reduced pressure and in vacuo to obtain tert-butyl[5-(chlorocarbonyl)-1,3-thiazol-2-yl]carbamate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:28])[N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:21][CH3:22])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.NCC1C=CN=C(CN(CCCCN(CC)CC)C(=O)OC(C)(C)C)C=1.[F:55][C:56]([F:62])([CH2:60][CH3:61])[C:57](O)=[O:58]>>[F:55][C:56]([F:62])([CH2:60][CH3:61])[C:57]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:28])[N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:21][CH3:22])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])[CH:4]=1)=[O:58]
Reactant: CCN(CCN(C)C)C(=O)CN(Cc1cc(CN)ccn1)C(=O)OC(C)(C)C
Reactant: CCC(F)(F)C(=O)O
Agent: CCN(CC)CCCCN(Cc1cc(CN)ccn1)C(=O)OC(C)(C)C
Product: CCN(CCN(C)C)C(=O)CN(Cc1cc(CNC(=O)C(F)(F)CC)ccn1)C(=O)OC(C)(C)C

Procedure:
By General Procedure Y from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N-({[2-(dimethylamino)ethyl](ethyl)carbamoyl}methyl)carbamate (prepared by synthetic route B (analogously to intermediate xii)) and 2,2-difluorobutanoic acid to get the title compound as colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.48 (m, 1H), 7.27 (m, 1H), 7.07 (m, 2H), 4.55 (m, 4H), 4.10 (m, 2H), 3.33 (m, 5H), 2.26 (m, 14H), 1.43 (m, 9H), 1.13 (m, 9H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]2[N:7]([CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(O)C.C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]2[N:7]([C:11]([Br:15])=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cccn2cc(C)nc12
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Oc1cccn2c(Br)c(C)nc12
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 8 -acetoxy-2-methylimidazo[l,2-a]pyridine (100 mg) in ethanol (1 ml) was added N-bromosuccinimide (103 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate) to give 8-acetoxy-3-bromo-2-methylimidazo[1,2-a]pyridine (123 mg) as oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][C:3]=1[Cl:14].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>O1CCCC1.C(N1C=CN=C1)(N1C=CN=C1)=O.COCCCN1CCC(N)CC1>[OH2:10].[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][CH2:29][O:28][CH3:27])[CH2:33][CH2:34]2)=[O:13])=[CH:4][C:3]=1[Cl:14]
Reactant: COCCCN1CCC(N)CC1
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCCN1CCC(NC(=O)c2cc(Cl)c(N)c3c2OCC3)CC1
Product: O
Temperature: 25 °C
Yield: 181.1 %

Procedure:
Reaction under N2 flow. 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.18 mol) was dissolved in tetrahydrofuran (360 ml) and this solution was stirred and cooled to ±3° C. 1,1'-Carbonylbis-1H-imidazole (0.18 mol) was added in one portion and cooling was stopped. The mixture was stirred for 75 minutes (became homogeneous after 30 minutes). A solution of 1-(3-methoxypropyl)-4-piperidinamine (0.18 mol) in tetrahydrofuran (90 ml) was added dropwise (exothermic temperature rise from 23° C. to 27° C.). The reaction mixture was stirred for 24 hours. More 1,1'-Carbonylbis-1H-imidazole (0.0125 mol) was added and the reaction mixture was stirred for 75 minutes. More 1-(3-methoxypropyl)-4-piperidinamine (0.0125 mol) was added (in 10 ml THF). The resulting reaction mixture was stirred for 3 hours at room temperature, then for 2.5 hours at reflux temperature. Then, the mixture was stirred for 13 hours, allowing it to cool to room temperature. The solvent was evaporated. The residue was stirred for 8 hours in water (360 ml) and the precipitate was filtered off, washed with water, then dried (vacuum; 30° C.), yielding 62.9 g (95%) 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrate; mp. 90.7° C. (comp. 2).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH:14]1([C:19](O)=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH:14]1([C:19]2[NH:1][C:2]3[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C1CCCC1
Reactant: CCCn1c(N)c(N)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C3CCCC3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After 30 g (163 mmol) of 5,6-diamino-1-propyl2,4-(lH,3H)-pyrimidinedione (Japanese Published Unexamined Patent Application No. 57517/80) was suspended in 600 ml of N,N'-dimethylformamide, 17.7 ml (163 mmol) of cyclopentanecarboxylic acid, 30.0 g (196 mmol) of hydroxybenztriazole and 50.5 g (245 mmol) of dicyclohexylcarbodiimide were added to the suspension. The mixture was stirred at room temperature overnight. After insoluble materials were filtered off, the filtrate was evaporated under reduced pressure. To the residue was added 600 ml of 4 N sodium hydroxide aqueous solution and the solution was refluxed for 10 minutes under heating. After ice cooling, insoluble materials were filtered off and 50 ml of methanol was added. The resulting mixture was neutralized with conc. hydrochloric acid. The precipitates were collected by filtration to afford 28.3 g (yield, 66%) of Compound c as a white powder.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=1
Reactant: OCc1ccc(OCCF)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FCCOc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4-(2-fluoroethoxy)phenyl)methanol (117 mg; 0.68 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (228 mg; 0.68 mmol), and with PPh3 (180 mg; 0.68 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 1-(bromomethyl)-4-(2-fluoroethoxy)benzene as a slightly yellow oil which was directly used for the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](I)=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[OH2:41].CN(C)[CH:44]=[O:45]>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30]([C:44]([OH:45])=[O:41])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: O
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(C(=O)O)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 60 °C
Yield: 69 %

Procedure:
To a stirring solution of 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide (0.51 g, 0.88 mmol) in N,N-dimethylformamide (13 mL) under argon was added dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol) and triethylamine (0.5 mL, 3.5 mmol) followed by water (3 mL). The reaction mixture was evacuated and placed under an atmosphere of carbon monoxide, heated at 60° C. for 3 h., and concentrated in vacuo. The resulting residue was partitioned between aqueous sodium bicarbonate and ethyl acetate and the layers separated. The aqueous phase was treated with a small amount of dichloromethane and then solid citric acid to pH 3. The resulting mixture was extracted with 3:1 chloroform:isopropanol. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with 2:4:0.5 ethyl acetate:toluene:acetic acid. The chromatography product was slurried in diethyl ether and filtered to give 0.31 g (69%) of a yellow solid.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C(O[CH:14]=[C:15]([C:21](=O)[CH:22]([CH3:24])[CH3:23])[C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])C>CO>[CH:17]([C:16]([C:15]1[C:21]([CH:22]([CH3:24])[CH3:23])=[N:9][CH:8]=[N:10][CH:14]=1)=[O:20])([CH3:19])[CH3:18]
Reactant: N=CN
Reactant: CCOC=C(C(=O)C(C)C)C(=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C(=O)c1cncnc1C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
11.5 g (60 mmol) of a 28% sodium methoxide solution was dissolved in 100 ml of methanol, and 5.6 g (54 mmol) of formamidine acetate was added, followed by stirring at room temperature for 15 minutes. Then, 11.5 g (54 mmol) of 4-ethoxymethylene-2,6-dimethyl-3,5-heptanedione was added under cooling with ice. The reaction mixture was further reacted at 50° C. for one hour. The solvent was distilled off under reduced pressure, and 200 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate=4:1) to obtain 9.2 g (yield: 89%) of 5-isopropylcarbonyl-4-isopropylpyrimidine as slightly yellow liquid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](C(=O)CC(OC)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:22][C:23]([O:25]CC)=[O:24].[O:28]1CC[CH2:30][CH2:29]1>>[N:1]1([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:29](=[O:28])[CH2:30][CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)CC(=O)c1ccc(-n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CCC(=O)c1ccccc1-n1ccnc1

Procedure:
A solution of methyl 4-(1H-imidazol-1-yl)-β-oxo-benzenepropanoate (6.1 g, 0.025 mol) in tetrahydrofuran (65 ml) is added slowly to a stirred suspension of 50% NaH (1.2 g, 0.025 mol) in tetrahydrofuran (20 ml) and the solution is stirred for one additional hour. Ethyl bromoacetate (4.5 g) is added followed by refluxing the mixture for seven to eight hours. The tetrahydrofuran is removed, the residue is treated with water, and the organic material is extracted with ether. The residue obtained after removal of the ether is hydrolysed by heating with 6N HCl for eight hours. The crude acid is finally crystallized from dimethylformamide to yield 3.3 g of the product 4-(1-imidazol-1-yl)-γ-oxobenzenebutanoic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.C1C[O:27]CC1>>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:27])=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1ccccc1Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1

Procedure:
A 1 M solution of lithium aluminum hydride in THF (258 ml, 258 mmol) was added dropwise to a solution of the mixture of 2-(4-fluorobenzyl)benzoic acid and the starting material 2-(4-fluorobenzoyl)benzoic acid, which was isolated in step 1, in THF (200 ml). The reaction mixture was heated to reflux for 2 hours. It was cooled to 0° C. Carefully, methanol (100 ml) and water (50 ml) were added successively. A 10% aqueous solution of sodium hydrogensulphate (500 ml) and a 1 N solution of sodium chloride in water were added. The phases were separated. The aqueous phase was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (600 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. 5.23 g of [2-(4-fluorobenzyl)phenyl]methanol were isolated by flash chromatography on silica (200 g), using ethyl acetate/heptane 1:1 as eluent.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+].[CH2:33](O)[CH3:34].O>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH3:5])[C:34]1[CH:33]=[CH:15][C:14]([C:2]2[C:7](=[O:8])[N:6]3[CH:9]=[CH:10][S:11][C:5]3=[N:4][C:3]=2/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:13][CH:12]=1
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)C
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(N(C)C)cc2)c1OCC(C)C

Procedure:
The title compound was prepared from Intermediate 7 (100 mg, 0.207 mmol), 4-N,N-dimethylaminophenylboronic acid (47 mg, 0.290 mmol), Pd[(C6H5)3P]4 (10 mg, 0.009 mmol) and sodium carbonate (131 mg, 1.244 mmol) in a mixture of toluene, ethanol and water according to the procedure outlined in Example 1 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 75 mg of the product; 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.9 Hz, 6H), 1.85-1.89 (m, 1H), 2.95 (s, 6H), 3.62 (d, J=6.3 Hz, 2H), 3.77 (s, 3H), 6.77 (d, J=9.0 Hz, 2H), 6.82-6.92 (m, 1H), 6.98-7.04 (m, 3H), 7.15 (d, J=9.0 Hz, 1H), 7.45 (d, J=4.8 Hz, 1H), 7.95 (d, J=4.8 Hz, 1H), 8.08 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 476.46 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:24]=[CH:23][C:22]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]OS(C)(=O)=O>>[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:24]=[CH:23][C:22]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCCOc1ccc(OCCCCCOS(C)(=O)=O)c(CCC(=O)OC)c1
Product: CCCc1c(OCCCCCOc2ccc(OCCCCC(=O)OC)cc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 61 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.66 g (1.4 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-5-(5-methoxy-5-oxopentyloxy)benzenepropanoic acid methyl ester (from example 57), 5-(5-methoxy-5-oxopentyloxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 61% yield (0.5 g) as a colorless solid. This diester (0.85 mmol) was saponified with 3 mL of 3N aqueous lithium hydroxide in 20 mL of tetrahydrofuran, at room temperature, for 24 hr. Work-up as in example 4 gave a crystalline acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.44 g (93%) of pure 5-(4-carboxybutoxy)-2-[5-[(3,4-dihydro-4-oxo- 8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid. Recrystallization from ethyl acetate gave 0.35 g (74%) of a colorless solid, mp 138°-139° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cnc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.6 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.0005 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 0.0025 mol) and allowed to stir r for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.151 g, 0.0012 mol) was added and stirred for further 3 h at 80 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC. to get the desired compound as yellow oil (0.025 g, 16% yield). 2,8-Dimethyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrid[4,3-b]indole (0.025 g, 0.000078 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0098 g, 0.000078 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.015 g, 47% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:20]=[O:21].[C:23]1([CH2:31]Cl)[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1>O>[C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:31][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][O:16][C:13]3[CH:12]=[CH:11][C:10]([C:9]([O:21][CH2:20][C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[O:8])=[CH:15][CH:14]=3)=[CH:25][CH:24]=2)=[CH:14][CH:15]=1)([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:17]
Reactant: CN(C)C=O
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: ClCc1ccc(CCl)cc1
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccc(COc3ccc(C(=O)OCc4ccccc4)cc3)cc2)cc1
Temperature: 100 °C
Yield: 33.2 %

Procedure:
To a solution of p-hydroxybenzoic acid benzyl ester (68.4 g, 0.3 mol) in N,N-dimethylformamide (274 g) sodium carbonate (15.9 g, 0.15 mol) was added, and stirred at 100° C. Then, p-xylylenedichloride (26.2 g, 0.15 mol) was added to the reaction mixture in 10 minutes, and stirred at 100° C. for one hour. Water was added to the resultant to separate a clued precipitate. The precipitate was filtered, added to N,N-dimethylformamide to be dissolved at 90° C., cooled, filtered, and dried to give a white crystal of 1,4-bis(p-carbobenzyloxyphenoxymethyl)benzene (27.8 g, yield 33.0): m.p. 154°-157° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[C:21]([O:30][CH2:31][CH2:32][OH:33])[N:20]=[C:19]([CH2:34][CH2:35][CH3:36])[N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:38]1[N:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1>O1CCCC1.CC(N(C)C)=O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[C:21]([O:30][CH2:31][CH2:32][O:33][C:38]3[N:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=3)[N:20]=[C:19]([CH2:34][CH2:35][CH3:36])[N:18]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1)([CH3:5])([CH3:6])[CH3:4]
Reactant: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccc(C)cc2)c(OCCO)n1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccc(C)cc2)c(OCCOc2ncc(Br)cn2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.4 %

Procedure:
To a suspension of sodium hydride (0.25 g) in tetrahydrofuran (5 ml) is added dropwise a solution of 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl]benzenesulfonamide (1.00 g) in dimethylacetamide (3 ml) and tetrahydrofuran (10 ml) at room temperature, and thereto is added 2-chloro-5-bromopyrimidine (0.56 g), and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is acidified with ice-cold diluted hydrochloric acid, and extracted with ethyl acetate. The extract is washed, dried, and evaporated to remove the solvent. The resulting oily product is purified by silica gel column chromatography (solvent; chloroform), and crystallized from n-hexane to give 4-tert-butyl-N-[6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl]benzenesulfonamide (1.21 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:19][NH:20][C@H:21]1[CH2:40][N:25]2[C:26]3[C:31]([C:32]([CH2:33][C:34]([O:36]CCC)=[O:35])=[C:24]2[CH2:23][CH2:22]1)=[CH:30][CH:29]=[CH:28][CH:27]=3>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([N:20]([CH3:19])[C@H:21]2[CH2:40][N:25]3[C:26]4[C:31]([C:32]([CH2:33][C:34]([OH:36])=[O:35])=[C:24]3[CH2:23][CH2:22]2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CN(C(=O)C(c1ccc(F)cc1)c1ccc(F)cc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from bis(4-fluorophenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 489.