Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.NC[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.C([N:29](C(C)C)CC)(C)C>C(#N)C.ClCCl>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:29][C:2]2[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=2)[CH2:14][CH2:15]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: NCC1CCN(Cc2ccccc2)CC1
Solvent: CC#N
Solvent: ClCCl
Product: FC(F)(F)c1nnc(NC2CCN(Cc3ccccc3)CC2)s1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
A mixture of 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (0.42 g, 2.24 mmol) (prepared by a procedure similar to that described in DE 82/3218482), 4-aminomethyl-1-benzylpiperidine (0.4 ml, 1.95 mmol) and diisopropylethylamine (0.5 ml, 2.90 mmol) in acetonitrile (6 ml) was stirred at 120° C. for 15 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by short open column chromatography (silica gel; 0-0.5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo to yield D3 (0.368 g, 48%) as a solid. C15H17F3N4S requires 342. Found 343 (MH+).
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH3:18][C@@H:19]1[N:22]([S:23]([O-:26])(=[O:25])=[O:24])[C:21](=[O:27])[C@H:20]1[NH:28][C:29]([O:31]C1C=CC=CC=1)=O.[CH2:38](N(CC)CC)[CH3:39].[CH3:45][Si](C)(C)Cl>ClCCCl>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[CH3:18][C@@H:19]1[N:22]([S:23]([O-:26])(=[O:25])=[O:24])[C:21](=[O:27])[C@H:20]1[NH:28][C:29](=[O:31])[CH2:45][C:17]1[CH:16]=[CH:15][CH:14]=[CH:39][CH:38]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCN(CC)CC
Reactant: C[C@H]1[C@H](NC(=O)Oc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCCl
Product: C[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1S(=O)(=O)[O-]

Procedure:
A solution of 531 mg (0.001 mole) of (3S-trans)-4-methyl-2-oxo-3-(phenyloxycarbonylamino)-1-azetidinesulfonic acid, tetrabutylammonium salt, in 15 ml of 1,2-dichloroethane is refluxed for 90 minutes with 278 μl of triethylamine and 250 μl of trimethylchlorosilane. After distillation of 5 ml of solvent, a solution of 136 mg of phenylacetic acid and 140 μl of triethylamine in 1 ml of dimethylformamide is added and the mixture is refluxed for 2 hours. The reaction mixture is poured into water and extracted into dichloromethane. After washing with saturated sodium bicarbonate solution, the organic layer is dried and evaporated. Trituration with ether gives 239 mg of (3S-trans)-4-methyl-2-oxo-3-(phenylacetylamino)-1-azetidinesulfonic acid, tetrabutylammonium salt.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([OH:12])[CH3:11])[C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C>C1COCC1.ClCCl.[O-2].[O-2].[Mn+4]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[O:12])[CH3:11])[C:4]=2[O:3][CH2:2]1
Reactant: CC(O)c1cccc2c1OCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a solution of 1-benzo[1,3]dioxol-4-ylethanol (11 g, 66.3 mmol) in 100 mL of THF was added 17.26 g of manganese dioxide (MnO2) in one portion and reaction was monitored by TLC. After several hours, TLC showed some product but significant alcohol left. More manganese dioxide was added and the solution stirred. TLC then showed mostly product but a significant amount of alcohol. The reaction mixture was then filtered through a bed of diatomaceous earth and the filtrate was concentrated in vacuo to give an oil that mostly crystallized on standing. To 9.24 mL of a solution of oxalyl chloride in 120 mL of dichloromethane at −60° C. was added a solution of 15 mL of DMSO in 20 mL of dichloromethane. After 10 minutes, a solution of above alcohol/ketone mixture (53 mmol) in 20 mL of dichloromethane was added, followed 15 minutes later by 44.3 mL of triethylamine. The reaction was allowed to slowly warm to room temperature overnight. The reaction mixture was then poured onto ice and the organic layer was washed with five 100 mL portions of water, then brine, and then dried over magnesium sulfate. The organics were concentrated in vacuo to leave tan solids and the solids were triturated with hexanes, collected by filtration, and dried to give 9.33 g (85.8% yield) of 1-benzo[1,3]dioxol-4-ylethanone.
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C[C:14]1[NH:15]C(C)=C(C(OCC)=O)C[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(CC(OCC)=O)#N.N1CCC[C@H]1C(O)=O>CS(C)=O>[C:14]([CH:19]([CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:15]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOC(=O)CC#N
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (3.4 g), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.0 g) and ethyl cyanoacetate (2.2 g) in dimethylsulfoxide (40 mL) was added L-proline (460 mg), and the mixture was stirred at room temperature for 48 hr. The insoluble substance was removed by filtration, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.3 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]([NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1)=[O:16].O>N1C=CC=CC=1>[CH:15]([NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]1)=[O:16]
Reactant: N[C@H]1CC[C@H](NC=O)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: c1ccncc1
Solvent: O
Product: O=CN[C@H]1CC[C@H](Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 4-fluoro-3-nitrobenzotrifluoride (900 mg) in pyridine (9 mL) was added trans-4-formamidocyclohexylamine (734 mg). The mixture was stirred at 100° C. under nitrogen atmosphere for 5 hours. After cooling to room temperature, water was added to the mixture. The resulting precipitate was collected by filtration and washed with water to give 4-[(trans-4-formamidocyclohexyl)amino]-3-nitrobenzotrifluoride (1.24 g) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:14][O:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C@@H:11]3[CH2:12][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][C@H:10]3[OH:13])=[CH:26][CH:27]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 40 g. of 1-benzyl-3,4-epoxypyrrolidine and 42 g. of 4-benzoxyphenol was heated at 130° C. for 8 hr. On cooling, the mixture crystallized. Three crystallizations from petroleum ether-cyclohexane gave fluffy white crystals melting at 98.0°-100.0° C. The yield was 6.0 g. (8%).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].N1C=CC=CC=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:5][CH2:1][CH:2]([OH:4])[CH3:3])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(C)O)cc1
Reaction time: 72 h

Procedure:
In 200 ml of methylene chloride were dissolved 38 g of 1,2-propanediol and 44 g of pyridine and, then, 95 g of p-toluenesulfonyl chloride was added gradually over a period of 15 minutes. The reaction was further conducted at room temperature for 72 hours. The reaction mixture was washed twice with one volume of water each, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was crystallized from toluene-hexane (100 ml-100 ml), filtered, and dried in vacuo to give colorless crystals of (RS)-1-p-toluenesulfonyloxy-2-propanol 2a ##STR21## (54 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].Cl.[OH2:12]>C1COCC1.C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:2]2[CH2:3][CH2:4][C:5](=[O:12])[CH2:6][CH2:7]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C1CCC(c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Grignard reagent was prepared from 50.0 g (259 mmol) of 3,5-difluorobromobenzene and 6.32 g (260 mmol) of dried magnesium in 350 ml of THF, and cooled down to 0° C. Solution of 40.6 g (260 mmol) of a commercially available cyclohexanedionemonoethylene ketal in 300 ml of THF was added dropwise thereto. After finishing of the dropping, the reaction product was warmed up to room temperature and stirred for 3 hours. The reaction product was added to 500 ml of 6N hydrochloric acid, the product was extracted with toluene, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and the solvent was distilled off. To the residue was added 100 ml of toluene and 5 g of p-toluene sulfonic acid (hereinafter abbreviated to PTS) and refluxed for 5 hours with the water formed by the reaction being removed by a Dean and Stark. Subsequently, 2 g of ethylene glycol was added and refluxed for 2 hours. To the reaction product was added 200 ml of water, the organic layer was washed with saturated aqueous sodium bicarbonate solution and water in turn, dried over magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography treatment using toluene/ethyl acetate (4/1) as eluent, and then subjected to hydrogenation in ethanol using 2.02 g of 5% Pd/C as catalyst. After termination of the reaction, the catalyst was filtered off, and the ethanol was distilled off. After the concentrated product thus obtained was refluxed in 150 ml of formic acid for 3 hours, 400 ml of water was added to the reaction product, the product was extracted with toluene, the extract was washed with saturated aqueous sodium bicarbonate solution and water in turn, the toluene layer was dried over magnesium sulfate, and then the toluene was distilled off to obtain 20.2 g (96.1 mmol) of 4-(3,5-difluorophenyl)cyclohexanone. Yield of this product from 3,5-difluorobromobenzene was 37.1%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:15]([C:10]1([CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH2:16][CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCCCC1(CCCC)CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCC1(CCCC)CNCCC1O

Procedure:
A mixture of 1-benzyl-3,3-di-n-butyl-4-hydroxypiperidine (0.9 g, 2.97 mmole) and 20% palladium hydroxide (0.2 g) in methanol (20 ml) was stirred at ambient temperature in hydrogen atmosphere (1 atm.) for 8 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-di-n-butyl-4-hydroxypiperidine as oil. Yield 0.5 g (85%), C14H27NO, m/z 214 (M+1).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C>[C:23]1(=[O:24])[N:19]([O:7][CH2:6][C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])[C:20](=[O:29])[C:21]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of thymidine (24.22 g, 0.1 mol), N-hydroxyphthalimide (21.75 g, 0.13 mol), triphenylphosphine (34 g, 0.13 mol) in dry DMF (400 ml) was added diisopropylazodicarboxylate (30 ml, 0.15 mol) over a period of 3 h at O° C. After complete addition the reaction mixture was warmed up to room temperature and stirred for 12 h. The solution was concentrated under vacuum (0.1 mm, <40° C.) to furnish an orange-red residue. The residual gum was washed several times with Et2O and washing were discarded. The semi-solid residue was suspended in EtOH (500 ml) and heated (90° C.) to dissolve the product. On cooling 30.98 g (80%) of 5'-O-phthalimidothymidine was collected in 3-crops as white crystalline material, mp 233°-235° C. (decomp.); H NMR (DMSO-d6) δ 11.29 (s, 1, NH), 7.85 (m , 4, ArH), 7.58 (s, 1, C6H), 6.20 (t, 1, H1', J1',2' =7.8 Hz, J1',2" =6.5 Hz), 5.48 (d, 1, OH3'), 4.36 (m, 3, H4',5',5"), 4.08 (m, 1, H3'), 2.09-2.13 (m, 2, H2',2"), and 1.79 (s, 3, CH3). Anal. Calcd. for C18 H17O7N3. 0.7 H2O: C, 54.05; H, 4.64; N, 10.51. Found: C, 53.81; H, 4.25; N, 10.39.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:2]1=2.[Cl:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:11][CH2:12][CH2:13][O:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: Oc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: ClCCOc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzo[b]thiophen-5-ol (0.5 g, 3.3 mmol, prepared in an analogous manner to a literature preparation: Synthetic Communications 21(7), 959-964, 1991) was dissolved in anhydrous acetonitrile (10 mL) was treated with chloroethyltosylate (0.94 g, 3.99 mmol) and cesium carbonate (2.15 g, 6.6 mmol). The mixture was stirred at reflux under nitrogen. After 2 h, the reaction was allowed to cool down to room temperature. The volatiles were removed in vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The ethyl acetate layer was then dried with sodium sulfate and purified by flash chromatography using a gradient of 5 to 25% of ethyl acetate in hexanes to obtain a white solid. Yield=0.676 g.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:27][C:28]1[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][C:29]=1[N+:37]([O-])=O>>[CH3:27][C:28]1[S:32][C:31]([S:33](=[O:35])(=[O:34])[NH2:36])=[CH:30][C:29]=1[NH:37][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1sc(S(N)(=O)=O)cc1[N+](=O)[O-]
Product: Cc1sc(S(N)(=O)=O)cc1NC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-methyl-thiophene-2-sulfonic acid amide (example B.11 ) according to general procedure II. Yellow solid. MS (ISP) 548.1 [(M−H)−]; mp 297° C.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:8]([CH2:23][CH3:24])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C>C1COCC1.CO>[CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][OH:21])=[CH:17][CH:18]=3)[CH:9]=[C:8]([CH2:23][CH3:24])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(Cc2ccc(CC(=O)O)cc2)nc(C2CCCC2)n1
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CCc1cc(Cc2ccc(CCO)cc2)nc(C2CCCC2)n1
Yield: 27.9 %

Procedure:
A solution of 2-(4-((2-cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)acetic acid (0.050 g, 0.15 mmol) in THF (5 mL) at rt under a nitrogen atmosphere was treated with BH3.SMe2 (0.047 g, 0.62 mmol) and the mixture was heated at 55° C. for 4 h. After this time, the mixture was cooled, diluted with methanol, and concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.013 g, 30%) as a yellow oil. MW=310.43. 1H NMR (DMSO-d6, 500 MHz) δ 7.22-7.17 (m, 2H), 7.16-7.11 (m, 2H), 7.00 (s, 1H), 4.58 (t, J=5.2 Hz, 1H), 3.93 (s, 2H), 3.60-3.53 (m, 2H), 3.21 (quin, J=8.1 Hz, 1H), 2.71-2.58 (m, 4H), 2.01-1.91 (m, 2H), 1.88-1.79 (m, 2H), 1.78-1.69 (m, 2H), 1.67-1.57 (m, 2H), 1.16 (t, J=7.6 Hz, 3H); APCI MS m/z 311 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16](=[O:26])[NH:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:13]=[C:12]([C:27](O)=[O:28])[CH:11]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[OH:63][CH:64]1[CH2:67][NH:66][CH2:65]1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([C:27]([N:66]2[CH2:67][CH:64]([OH:63])[CH2:65]2)=[O:28])[CH:13]=[C:14]([C:16]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:26])[CH:15]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)c(C#N)c1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CC(O)C3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask was charged with 2′-cyano-4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (80 mg, 0.24 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol), 1-hydroxybenzotriazole hydrate (64 mg, 0.42 mmol), N,N-diisopropylethylamine (110 mg, 0.83 mmol), methylene chloride (5 mL) and 3-hydroxyazetidine hydrochloride (45 mg, 0.42 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[N:25]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:32][CH2:33]2)=[O:12])[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1cccc2cc[nH]c12)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a chilled solution of indole-7-carboxylic acid (3.22 g; 0.02 mole) in 30ml dimethylformamide was added 1,1'-carbonyldiimidazole (3.24 g; 0.02 mole). This was stirred at ice bath temperature for 40 minutes after whicha solution of 1-(2-pyrimidyl)piperazine (4.1 g; 0.025 moles) was added. This was stirred at ambient temperature for 3 hours and the solvent was concentrated in vacuo. The resulting oil was triturated with water to give5.7 g (93%) of a solid, m.p. 194°-197° C. The solid was recrystallized from methanol/water to give 4.7 g (76%) of 1-(1H-Indol-7-ylcarbonyl)-4-(2-pyrimidinyl)piperazine, m.p. 200°-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:16][O:17][CH2:18]Cl.CN(C=[O:24])C>>[CH3:16][O:17][CH2:18][O:13][C:5]1([OH:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH2:4]1
Reactant: COCCl
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COCOC1(O)C=C(OC)C(OC)=C(OC)C1
Temperature: 0 °C

Procedure:
25 g of 3,4,5-trimethoxyphenol was dissolved in 100 ml of DMF, and 7.1 g of sodium hydride (55% oil suspension) was added thereto and cooled by ice while stirring. Then, 12.4 ml of methoxymethyl chloride was added thereto with ice cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=85:15) to prepare 30.4 g of the product compound as a colorless oleaginous substance.
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].C([O:18][C:19](=[O:51])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:51])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 59.3 %

Procedure:
Starting with 0.128 g (0.62 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.349 g (0.62 mmol) of 2-[(8-bromooctyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.232 g; 76.3% overall yield) was obtained as a white solid, mp 112°-117° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.