Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[CH2:5][C:6]1[CH:11]=[C:10]([CH:12]=[CH2:13])[CH:9]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:5][C:6]1[CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1)[CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39]
Reactant: C=Cc1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)C(=O)OC)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)C(=O)OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(trifluoromethyl)-5-vinylbenzyl]carbamate (14 mg, 0.025 mmol) (Example 44) and Pd/C (5 mg) in THF (1 mL) and MeOH (500 μL) was placed under hydrogen. The reaction was stirred at room temperature under hydrogen for two hours. The reaction was then diluted with hexanes (25 mL), loaded on a silica gel column, and purified with 20% EtOAc/hexanes to afford methyl[3-ethyl-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.31 (25% EtOAc/hexanes). LCMS=568.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.72 (broad singlet, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 7.07 (d, J=8.0Hz, 1H), 7.01 (dd, J=2.0 Hz, 8.5, 1H), 7.01 (broad singlet, 1H), 6.86 (d, J=2.5 Hz, 1H), 6.59 (d, J=8.5 Hz, 1H), 4.44 (broad singlet, 2H), 4.11 (broad singlet, 2H), 3.39 (s, 3H), 3.24 (s, 3H), 2.73 (m, 1H), 2.25 (q, J=7.5 Hz, 2H), 1.15 (d, J=7.0 Hz, 6H), 0.92 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14](O)[CH2:15]C=C)=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.CSC.[C:31](=[O:34])([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][CH:31]=[O:34])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: C=CCC(O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CSC
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=CC=O
Reaction time: 2 h
Yield: 96.1 %

Procedure:
N-[4-(4-fluorophenyl)-5-(1-hydroxybut-3-enyl)-6-isopropyl-pyrimidin-2-yl]-N-methylmethanesulfonamide (4 g, 10.2 mmol) is diluted in 102 mL methanol. O3 gas is bubbled through the solution at −15° C. to −10° C. for 60 min. Reaction solution is bubbled through with Argon for 2 min to remove the excess of O3. Dimethylsulfide (1.5 ml, 20.3 mmol) is added to the solution, maintaining stirring for 2 hours. To the reaction mixture, potassium carbonate (2.8 g, 20.3 mmol) is added at room temperature. The progress of the reaction is monitored by TLC. Upon completion of the reaction, 150 ml sodium bicarbonate (aq.) is added and methanol is distilled off under reduced pressure. The residue is extracted with ethyl acetate (2×300 mL) and washed with DM water (100 mL) and brine (150 mL). The organic solvent is distilled off under reduced pressure to give 3.7 g (95%) of N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methyl-methanesulfonamide The product is recrystallized from 20% ethylacetate:cyclohexane at 0° C. to 5° C. to afford 2.4 g (67%) of N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methyl-methanesulfonamide as an oily white-yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:12]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13]1)=[N:10][OH:11].[OH-].[K+].O.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13]3)=[N:10][O:11][C:2]=2[CH:7]=1
Reactant: ON=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1ccc2c(C3CCN(Cc4ccccc4)C3)noc2c1
Yield: 74.8 %

Procedure:
A mixture of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime (10.8 g, 34.2 mmol), potassium hydroxide (10 g), water (100 ml), and ethanol (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the solution was cooled and ethanol was removed on a rotary evaporator. The aqueous mixture was diluted with water (100 ml) then extracted with dichloromethane (500 ml). The organic solution was washed with brine and dried over anhydrous MgSO4. The solution was concentrated to an oil (9.8 g). The crude product was purified by flash chromatography over a silica gel column. The product thus obtained weighed 4.46 g (44%) as a light yellow oil. The oily product was dissolved in ethanol, and then treated with a solution of fumaric acid (1.73 g, 1.0 eq) in ethanol. Crystallization took place slowly with the addition of isopropyl ether. Recrystallization from ethanol (15 ml) gave 4.6 g of 6-fluoro-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate as white crystals, m.p.=142°-144° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:20][C@@H:19]([C:21]3[CH:32]=[CH:31][C:24]4[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=4[CH:22]=3)[O:18][C:17]2=[O:33])=[CH:10][CH:9]=1)(=O)C.O([Si](C)(C)C)[K].P([O-])([O-])([O-])=O.O>C1COCC1>[CH3:29][C:26]1([CH3:30])[O:25][C:24]2[CH:31]=[CH:32][C:21]([C@H:19]3[O:18][C:17](=[O:33])[N:16]([CH2:15][CH2:14][C:11]4[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:13][CH:12]=4)[CH2:20]3)=[CH:22][C:23]=2[CH2:28][O:27]1
Reactant: CC(=O)OCCOc1ccc(CCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)cc1
Agent: C[Si](C)(C)O[K]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCO)cc4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethyl acetate (3.7 g) in THF (100 mL) was treated with KOSiMe3 (1.39 g) and stirred at room temperature for 3 h. The solution was then poured into phosphate buffer (pH 6.5) and water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo to give the title compound (3.31 g). LCMS RT=2.91 min.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:6]=1[NH:7][C:8]1[C:9]([C:16]([O:18]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:10][N:11]([CH3:15])[C:12](=[O:14])[CH:13]=1>C1COCC1>[F:4][C:5]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:6]=1[NH:7][C:8]1[C:9]([C:16]([N:2]([CH3:3])[CH3:1])=[O:18])=[CH:10][N:11]([CH3:15])[C:12](=[O:14])[CH:13]=1
Reactant: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(I)cc2F)cc1=O
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
Dimethylamine (40% in aqueous solution) was added to 2,3,4,5,6-pentafluorophenyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate in THF as for example 37, step B, and the solution stirred at RT for 15 h. The resultant precipitate was removed by filtration and washed with hexane and Et2O. The filtrate was concentrated under reduced pressure and triturated with hexane to give 4-(2-fluoro-4-iodoanilino)-N,N,1-trimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a pale yellow solid (58%); m.p. 106-111° C. (glue-liquid). 1H NMR [400 MHz, (CD3)2SO] δ 8.21 (s, 1H), 7.79 (s, 1H), 7.72 (dd, J=10.2, 1.9 Hz, 1H), 7.56 (dt, J=8.4, 1.2 Hz, 1H), 7.16 (t, J=8.4 Hz, 1H), 5.41 (d, J=1.2 Hz, 1H), 3.34 (s, 3H), 2.98 (s, 6H). HRMS (FAB+) calcd for C15H16FIN3O2 416.0271 (M+), found 416.0270. HPLC 97.2% (254 nm).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].Cl>O.CN(C)C=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: COc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
To a mixture of 5-fluoro-2-nitrotoluene (7.0 grams, 45 mmol), 4-methoxyphenol (6.2 grams, 50 mmol) and dimethylformamide (45 mL) was added potassium tert-butoxide (5.1 grams, 45 mmol). After stirring at room temperature for 24 hours, the mixture was diluted with water, acidified with 1 M aqueous hydrochloric acid, and the aqueous phase was extracted 3 times with ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography eluting with 0-20% ethyl acetate-hexane afforded 3.5 grams of 4-(4-methoxy-phenoxy)-2-methylnitrobenzene as a yellow solid.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(O)C>[CH:13](=[N:3][NH:2][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 2-hydrazino-benzoic acid mono hydrochloric acid salt (13.66 g, 72.42 mmol) dissolved in water (580 mL) and ethanol (125 mL) was added a solution of benzaldehyde (7.35 mL, 72.42 mmol) in ethanol (20 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for an additional 3 hours. The resulting solid was collected by filtration and dried in a vacuum oven to provide 12.0 g (69%) of 2-(N′-benzylidene-hydrazino)-benzoic acid as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6][C:5]2[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.C(N=[C:21]=[O:22])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[CH3:1][C:2]1([CH3:15])[S:6][C:5]2[C:7]([S:11]([N:14]=[C:21]=[O:22])(=[O:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2cccc(S(N)(=O)=O)c2S1
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CC1(C)Cc2cccc(S(=O)(=O)N=C=O)c2S1

Procedure:
To a refluxing solution of 8.6 g of 2,3-dihydro-2,2-dimethyl-7-benzo[b]thiophenesulfonamide (Example 14), 4.0 ml of n-butylisocyanate and 0.1 g of DABCO in 100 ml of xylenes was added 3.0 ml of phosgene at such a rate that the reaction temperature did not drop below 135° C. The mixture was refluxed for 1.5 hours, then the excess phosgene was purged with a stream of dry nitrogen. The mixture was cooled, filtered and concentrated in vacuo to yield the title compound as an oil. The crude yield was assumed to be near quantitative. IR (neat) 2220 cm-1 (NCO).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:15]2=[O:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.CO.Cl.[H][H]>[Pd].O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:27])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: COc1ccc(N2CCN(C3CCN(Cc4ccccc4)CC3)C2=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(N2CCN(C3CCNCC3)C2=O)cc1

Procedure:
A mixture of 44 g of 1-(1-benzyl-4-piperidyl)-3-(4-methoxy-phenyl)-imidazolidin-2-one, 320 ml of methanol, 130 ml of water and 12 g of a conc. aqueous solution of hydrochloric acid, with the addition of 10 g of a palladium on charcoal catalyst, is hydrogenated at 30° to 40° C and under reduced pressure until 1 molar equivalent of hydrogen has been taken up. Thereafter the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from a mixture of isopropyl alcohol and diethyl ether to yield the 1-(4-methoxyphenyl)3-(4-piperidyl)-2-imidazolidinone with a melting point of 140° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[C:12]=[O:13]>C1COCC1>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:11][C:12]([N:2]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1)=[O:13]
Reactant: Cc1ccccc1CN=C=O
Reactant: Oc1n[nH]c2ccccc12
Solvent: C1CCOC1
Product: Cc1ccccc1CNC(=O)n1[nH]c2ccccc2c1=O

Procedure:
105 mg (0.78 mmol) of 1H-indazol-3-ol were reacted in 3 ml of THF with 138.3 mg (0.94 mmol) of 1-isocyanatomethyl-2-methylbenzene to give 3-oxo-1,3-dihydro-indazole-2-carboxylic acid 2-methylbenzylamide. 50 mg (178 μmol) of this compound were stirred in 3 ml of pyridine with 40 mg (355 μmol) of triethylamine and 43 mg (266 μmol) of 4-methylpiperidine-1-carbonyl chloride at room temperature for 7 h. Addition of a further 120 mg of 4-methylpiperidine-1-carbonyl chloride and 100 mg of triethylamine in 3 portions was followed by stirring again for 7 h, concentration and purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 48 mg (66%), M+H+: 407.15.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:25][OH:26].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:26][NH:25][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(CCc3ccccc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NO)c1cnc(N2CCN(CCc3ccccc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15e (125 mg, 0.377 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (262 mg, 3.77 mmol) and a freshly prepared solution of sodium methoxide in methanol (130 mg, 5.655 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16e.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[O:11])[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=1.Cl>O1CCCC1.O>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]([CH:16]([CH3:17])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[O:11])[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(-c2c(N)cc(C(=O)N(C(C)C)C(C)C)cc2[N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C(=O)c1cc(N)c(-c2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1)C(C)C
Yield: 84.5 %

Procedure:
0.64 ml of 2N sodium hydroxide were added to a solution of 235 mg of product A in 4 ml of tetrahydrofuran and the mixture was heated under refluxed for 2 hours. Then, the reaction mixture was diluted with 10 ml of water and the pH was adjusted to 9 with 1N hydrochloric acid. Washing was carried out with ethyl acetate and the pH is adjusted to 5 with 1N hydrochloric acid. Extraction was carried out with ether and the ethereal phases were dried with MgSO4, followed by evaporation under reduced pressure. The residue was crystallized from ether to obtain 191.7 mg of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH:7]([CH2:13][C:14](=O)[CH3:15])[CH2:6]2.O.[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1[N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[C:14]([CH3:15])=[CH:13][C:7]=1[CH2:6]2
Reactant: COc1ccc2c(c1)CC(CC(C)=O)C2=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)Cc1cc(C)n(CC(C)O)c1-2
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A solution of 1.2 g of (RS)-5-methoxy-2-(2-oxopropyl)-1-indanone and 60 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 1.65 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 3 hours, during which the solvent was reduced to a volume of 30 ml. The cold reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.17 g (82%) of (RS)-1-(6-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([OH:12])=O)(=[O:3])[CH3:2].CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:78])([F:77])[C:49]1[CH:50]=[C:51]([C:59]([CH3:76])([CH3:75])[C:60]([N:62]([CH3:74])[C@H:63]2[C@H:67]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:66][NH:65][CH2:64]2)=[O:61])[CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1>C1COCC1>[C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([N:65]1[CH2:66][C@@H:67]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C@H:63]([N:62]([CH3:74])[C:60](=[O:61])[C:59]([C:51]2[CH:50]=[C:49]([C:48]([F:78])([F:47])[F:77])[CH:54]=[C:53]([C:55]([F:56])([F:57])[F:58])[CH:52]=2)([CH3:76])[CH3:75])[CH2:64]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Reactant: CC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@H](O)C[C@H]1C(=O)N1C[C@@H](N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Reaction time: 48 h
Yield: 29 %

Procedure:
To a stirred solution of (2S,4R)-1-acetyl-4-hydroxy-pyrrolidine-2-carboxylic acid (commercially available) (7.5 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 7.6 mg (29%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:45])[CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27][CH2:26]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:45])[CH:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:27][CH2:26]3)[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CCC(CCBr)CC1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(CCC2CCN(C(=O)C(c3ccccc3)c3ccccc3)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
Ethyl 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionate (100 mg; 0.38 mmol) was dissolved in absolute DMF (2 ml). Sodium hydride (50%; 19 mg; 0.38 mmol) was added, and the reaction mixture was stirred at RT for 1 h. Then 1-[4-(2-bromoethyl)piperidin-1-yl]-2,2-diphenylethanone (148 mg; 0.38 mmol) dissolved in absolute DMF (1 ml) was added. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The residue was taken up in 1N HCl and washed with dichlormethane (CH2Cl2; 2×). The aqueous phase was made basic with 1N NaOH and extracted with CH2Cl2 (3×). The combined organic phases were dried over Na2SO4. Removal of the solvent under reduced pressure resulted in ethyl 3-(6-aminopyridin-3-yl)-2-{1-[2-(1-diphenylacetylpiperidin-4-yl)ethyl]-1H-imidazol-4-yl}propionate (71 mg; 0.12 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:9].[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: Cc1cc[n+]([O-])c(Cl)c1
Reactant: NCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: Cc1cc[n+]([O-])c(NCCCO)c1
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A mixture of 2-chloro-4-methylpyridine-N-oxide (12.1 g, 0.068 mole) (Brown, E. V. J. Amer. Chem. Soc. 1957, 79, 3565), 3-amino-1-propanol (10.33 mL, 0.14 mole), NaHCO3 (28 g, 0.34 mole), and tert-amyl alcohol (70 mL) was heated to reflux. After 16 hr, the reaction was cooled, diluted with CH2Cl2 (300 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene to leave a yellow oil. Recrystallization from CH2Cl2/Et2O gave the title compound (10.87 g, 88%) as a yellow solid: TLC (15% MeOH/CH2Cl2) Rf 0.44; 1H NMR (400, CDCl3) δ 7.92 (d, J=6.7, 1 H), 7.28 (br t, 1 H), 6.43 (s, 1 H), 6.33 (dd, J=6.6, 2.1 Hz, 1 H), 3.73 (t, J=5.7 Hz, 2 H), 3.47 (q, H=6.3 Hz, 2 H), 2.29 (s, 3 H), 1.82-1.88 (m, 2 H); MS (ES) m/e 183 (M+H)+.
Reaction SMILES: [OH2:1].[OH:2][CH2:3][CH:4]([CH2:6][OH:7])[OH:5]>>[OH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:6]([C@@H:4]([CH2:3][OH:2])[OH:5])[OH:1])[OH:7])[OH:5]
Reactant: OCC(O)CO
Reactant: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
A gel vehicle containing about 25-28% water (apart from water provided as humectant solvent), about 10-12% of 99.5% glycerine solution and about 30-35% of 70% sorbitol solution can readily provide a refractive index of about 1.43 to 1.46 and permit formation of a clear gel dentifrice in which the refractive index of the polishing agent is about 1.41 to 1.47 and within 0.02 of the refractive index of the liquid vehicle.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][NH:24][CH3:25])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:26]([CH3:29])(=[O:28])=[O:27].CCN(CC)CC.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][N:24]([CH3:25])[S:44]([C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.7 %

Procedure:
To secondary amine 30 (150 mg, 0.35 mmol, 1 eq.) in dry DCM (15 mL) at 0° C. was added Et3N (3 mL) followed by dropwise addition of a DCM solution of 4-fluorobenzenesulfonyl chloride (90 mg, 0.42 mmol, 1.2 eq). After stirring at 0° C. for 20 min, the mixture was stirred at room temperature for 2 h. The reaction was extracted between DCM and water and the organic layer was washed with 1N HCl, saturated NaHCO3 solution, and brine, dried (Na2SO4), and concentrated in vacuo to give 150 mg (72%) of t-butyl 2-((4-fluoro-3-(methylsulfonyl)phenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (31) as oil which was used in the next step without further purification.