Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)[O:21][C:20]1([CH3:35])[CH3:34])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>ClCCl>[F:25][CH2:24][C@@H:23]1[C@@H:22]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:33])=[O:9])=[CH:30][CH:31]=2)[O:21][C:20]([CH3:35])([CH3:34])[N:19]1[C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (14.3 g, 1.2 eq) in 100 ml of dichloromethane was added drop wise to the solution of 13 (17.3 g) in 150 ml of dichloromethane at −20° C. The temperature was maintained at −20° C. for an additional 40 minutes. A saturated solution of sodium bicarbonate (80 ml) was added and stirred for 30 minutes. The organic layer was separated and washed with brine (50 ml) and dried over sodium sulfate. After purification (via a column) 13.4 g of the desired product (as a heavy oil) was obtained.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.S(Cl)([Cl:22])=O.CN(C)C=O>ClCCl>[ClH:22].[ClH:1].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:22])=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(C(=O)Cl)cc2)CC1

Procedure:
A mixture of 4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride (50 g), thionyl chloride (200 ml) and N,N-dimethylformamide (12.5 ml) was refluxed for 20 hours. After completion of reaction, the reaction mass was distilled out completely under vacuum to give residue which was diluted with dichloromethane (100 ml). Solid thus precipitated was filtered and washed to give 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride. To a mixture of 4-Methyl-N-(4-pyridin-3-yl-pyridin-2-yl)benzene-1,3-diamine (20 g) in dichloromethane (500 ml), potassium carbonate (80 g) was added and stirred for 30 minutes. 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride (prepared above) was added to the reaction mass at 0-5° C. and refluxed for 10 hours. After completion of reaction, reaction mass was quenched with dilute hydrochloric acid (420 ml) up to pH 1.0-3.0 and layers were separated. Aqueous layer was washed with dichloromethane, diluted with tetrahydrofuran (120 ml) and basified up to pH 8.0-8.5 with 10% sodium hydroxide solution (200 ml). Solid thus precipitated was filtered, washed with sodium hydroxide solution and demineralised water to give title compound having amine intermediate: 39.7 ppm).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1>>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH:14]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCc1cccnc1
Product: O=C(O)c1ccc(OCc2cccnc2)nc1
Yield: 66 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 66% yield starting from ethyl 6-chloronicotinate and pyridine-3-methanol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67-8.76 (m, 2 H), 8.54 (d, 1 H), 8.17 (dd, 1 H), 7.89 (d, 1 H), 7.42 (dd, 1 H), 6.98 (d, 1 H), 5.47 (s, 2 H); (APPI/APCI) m/z 231[M+H+].
Reaction SMILES: C([O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CON(C)C(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
10% Palladium on charcoal (4.5 g) in methanol (10 mL) was treated with the product from Example 71B (18.60 g, 68.55 mmol) in 150 mL methanol. The mixture was placed under hydrogen atmosphere at 67 psi. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography to provide the title compound (10.3 g, 83% yield). 1HNMR (300 MHz, CD3OD) δ 3.32 (s, 3H), 3.58 (s, 3H), 6.81 (d, 2H, J=8.9 Hz). 7.59 (d, 2H, J=8.9 Hz); MS (DCI) m/z 182 (M+H)+, 199 (M+NH4)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[N:7][C:8]=1[CH2:9]Cl.[Cl:18][C:19]1[C:20]2[CH2:27][C:26](=[O:28])[NH:25][C:21]=2[N:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:18][C:19]1[C:20]2[C@:27]3([CH2:9][C:8]4=[N:7][CH:6]=[C:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:4]=[C:3]4[CH2:2]3)[C:26](=[O:28])[NH:25][C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: CC(C)(C)OC(=O)c1cnc(CCl)c(CCl)c1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncnc(Cl)c21
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 5,6-bis(chloromethyl)pyridine-3-carboxylate (1.80 g, 6.52 mmol) in N,N-dimethylformamide (93.0 mL) was added 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (1.80 g, 10.62 mmol), cesium carbonate (3.65 g, 11.21 mmol), and sodium bromide (0.671 g, 6.52 mmol). After 30 min, saturated aqueous sodium bicarbonate was added and the mixture was washed with ethyl acetate (3×). The combined organics were washed with water (3×), brine (3×) and were dried with magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→10% methanol/dichloromethane) then a second purification by silica gel chromatography (100% dichloromethane→30% ethyl acetate/dichloromethane) gave the title compound as a racemic mixture. Chiral separation of the individual enantiomers was accomplished by use of HPLC using a 10 cm ChiralPak® AD column (60% EtOH/hexanes with 0.1% diethylamine) to give the title compound as the 1st eluting enantiomer. MS: m/z=373.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=CC=C[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1CC1)#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][CH:25]2[CH2:30][CH2:26]2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Agent: C#CC1CC1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: C(#CC1CC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and ethynylcyclopropane.
Reaction SMILES: [Li]CCCC.C(=O)=O.CC(C)=O.Br[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=1.[CH3:21][C:22]([Si:25]([CH3:31])([CH3:30])[O:26][CH2:27][CH:28]=[O:29])([CH3:24])[CH3:23].CC(O)=O>C1COCC1.CO>[Br:20][C:16]1[N:15]=[C:14]([CH:28]([OH:29])[CH2:27][O:26][Si:25]([C:22]([CH3:23])([CH3:21])[CH3:24])([CH3:30])[CH3:31])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Brc1cccc(Br)n1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC(O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of nBuLi (7.90 mL of a 1.6M solution in hexanes, 12.64 mmol) in THF (7.6 mL) was cooled to −78° C. (dry-ice/acetone bath) under nitrogen and then treated with a solution of 2,6-dibromopyridine (3.00 g, 12.66 mmol) in THF (17.8 mL) drop-wise over 30 min. The resulting green solution was stirred at −78° C. for 20 min and then treated with {[(1,1-dimethylethyl)(dimethyl)silyl]oxy}acetaldehyde (3.00 mL, 15.75 mmol) over 1 min to give a deep purple/brown coloured solution which was stirred at this temperature for 15 min. The reaction was then quenched by the addition of a mixture of MeOH (12.5 mL) and AcOH (0.8 mL, 13.90 mmol) in one portion and the resulting clear, pale yellow solution allowed to warm slowly to ambient temperature over 1.25 h. The mixture was then partitioned between EtOAc (100 mL) and saturated aqueous NH4Cl (100 mL), and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with brine (200 mL), dried (MgSO4), filtered and reduced to give the title compound as a clear, pale yellow oil which was used directly without further purification (4.61 g).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([C:25]([C:30]2[N:31]=[CH:32][N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:34]=2)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:19]=[CH:18]3)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO.[OH-].[Na+]>C1COCC1.CO>[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C:25]([C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:19]=[CH:18]2
Reactant: CC(C)C(O)(c1ccc2cc(N=C(c3ccccc3)c3ccccc3)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2cc(N)ccc2c1)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 176 %

Procedure:
1-{6-[(Diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.0 g) was dissolved in THF (5 ml)-methanol (5 ml). To the solution were added sodium acetate (285 mg) and hydroxylamine hydrochloride (181 mg), and the mixture was stirred at room temperature for 20 min. To the mixture was added 0.1N-aqueous solution of sodium hydroxide, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried. The solvent was distilled off and the residue was purified by silica gel chromatography (eluent, hexane:ethyl acetate=2:1→1:1) to give the titled compound (720 mg) as a pale red powder.
Reaction SMILES: [Cl:1][CH:2]([C:7]1[CH:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[N:9]2[CH:12]([CH:13]=1)[CH:11]([CH:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH3:15])[C:10]2=[O:27])[C:3]([O:5][CH3:6])=[O:4]>C(OCC)C>[Cl:1][C:2](=[C:7]1[CH2:13][CH:12]2[N:9]([C:10](=[O:27])[CH:11]2[CH:14]([O:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH3:15])[CH:8]1[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)=[O:29])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)C1=CC2C(C(C)OC(=O)OCc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: COC(=O)C(Cl)=C1CC2C(C(C)OC(=O)OCc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound is prepared by the procedure of Example 41, using 0.165 g of product from Example 42, 0.041 g (40 μl) of 1,8-diazobicyclo[5.4.0]-undec-7-ene, 20 ml of diethyl ether. The organic layer is concentrated in vacuo to give 0.140 g (85%) of product as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([F:20])[CH:19]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([N+:14]([O-])=O)=[C:10]([CH:13]=1)[C:11]#[N:12]>O1CCOCC1.[Pd]>[NH2:14][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:17]=[C:18]([F:20])[CH:19]=[C:2]([F:1])[CH:3]=2)=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1cc(Oc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: N#Cc1cc(Oc2cc(F)cc(F)c2)ccc1N
Yield: 70.7 %

Procedure:
5-(3,5-Difluoro-phenoxy)-2-nitro-benzonitrile (7.65 g, 27.7 mmol) in dioxane (80 mL) was treated with 10% Pd/C (765 mg) and hydrogenated at 45 psi. After 6 hours the reaction was filtered through a celite funnel and washed with MeOH. The volatiles were evaporated. After purification over silica gel (eluent: hexane:EtOAc 7:3), 4.82 g of title compound were obtained as a pale yellow solid in 71% yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1.[S:17]([O-:20])([O-:19])=[O:18].[Na+:21].[Na+]>CO>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:17]([O-:20])(=[O:19])=[O:18])=[CH:4][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:21]
Reactant: O=S([O-])[O-]
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: [Na+]
Solvent: CO
Product: O=S(=O)([O-])Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A mixture of α-bromo-4-fluoro-3-phenoxytoluene (4.86 g, 17.3 mmol) and sodium sulfite (2.39 g, 19 mmol) in 50% aqueous methanol (20 ml) is heated at reflux for 5 hours and cooled to room temperature. The resultant colorless solid is collected by filtration and washed with chilled 50% aqueous methanol and methanol to obtain 3.4 g of sodium (4-fluoro-3-phenoxyphenyl)methanesulfonate. Another 1.8 g of product is recovered from the mother liquors.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C([O-])([O-])=O.[K+].[K+].[C:12]([O:16][C:17](=[O:33])[N:18]([CH2:22][C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:25][C:24]=1[Cl:32])[CH:19]1[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>CC(C)=O>[CH3:5][O:4][C:2](=[O:3])[NH:31][CH2:30][CH2:29][C:27]1[CH:26]=[CH:25][C:24]([Cl:32])=[C:23]([CH2:22][N:18]([C:17]([O:16][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:33])[CH:19]2[CH2:20][CH2:21]2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCN)ccc1Cl)C1CC1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)NCCc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
Methyl chloroformate (1.72 mL, 21.9 mmol) and K2CO3 (7.65 g, 54.8 mmol) were added to a sol. of [5-(2-amino-ethyl)-2-chloro-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (1.78 g, 5.48 mmol) in acetone (8.00 mL). The mixture was refluxed overnight, and was allowed to cool to rt. The mixture was partitioned between water and CH2Cl2, and the aq. layer was extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 6:4) yielded the title compound (1.41 g, 67%). LC-MS: tR=1.03 min; ES+: 383.50.
Reaction SMILES: [P:1]([O:19][CH2:20][C:21](=[O:46])[C@@H:22]([NH:30][C:31](=[O:45])[C@H:32]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].CO>C(OCC)(=O)C.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[P:1]([O:19][CH2:20][C:21](=[O:46])[C@@H:22]([NH:30][C:31](=[O:45])[C@H:32]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:3])([OH:11])=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)COP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)COP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
A suspension of 30 mg of 20% Pd(OH)2 in a solution of dibenzyl (3S)-[3-[(N-t-Butoxycarbonyl-L-leucyl)amino]-2-oxo-4-phenylbutyl] phosphate (30 mg, 0.046 mmol) in 1.0 mL of ethyl acetate was stirred under H2 (1 atm) at room temperature for 4 hours. The catalyst was filtered through Celite™ and the filtrate was concentrated to give the crude product. Flash chromatography (10% MeOH in CH2Cl2) gave 8 mg of pure product. MS: 471 m/z (M-1).
Reaction SMILES: C1C=C2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OS(=O)(=O)C2=CC=1.N[C@H:27]([C:33]([OH:35])=[O:34])[CH2:28][CH2:29][C:30](=O)N.C(=O)=O.C[C@H:40]1[C@@H:61]([CH2:62]C2OC3C=CC(NC)=C(C(O)=O)C=3N=2)[O:60][C@:43]2([O:48][C@H:47]([C@@H:49]([C:51]([C:53]3NC=[CH:55][CH:54]=3)=[O:52])C)[C@H:46](C)[CH2:45][C@H:44]2C)[CH2:42][CH2:41]1>CS(C)=O>[CH3:62][CH2:61][CH2:40][CH2:41][CH2:42][C@H:43]([OH:60])/[CH:44]=[CH:45]/[C@@H:46]1[C@@H:53]([CH2:54]/[CH:55]=[CH:30]\[CH2:29][CH2:28][CH2:27][C:33]([OH:35])=[O:34])[C:51](=[O:52])[CH2:49][C@H:47]1[OH:48]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CNc1ccc2oc(C[C@H]3O[C@@]4(CC[C@H]3C)O[C@H]([C@H](C)C(=O)c3ccc[nH]3)[C@H](C)C[C@H]4C)nc2c1C(=O)O
Agent: O=C=O
Agent: O=S1(=O)OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Solvent: CS(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 8 h

Procedure:
3T3 Swiss Albino fibroblast cell suspension (Phenol-red free DMEM with 10% FBS and 2 mM L-glutamine) was plated out into 96-well tissue culture plates (1×105 cells/mL, 100 μL/well). The cells were cultured overnight at 37° C., 5% CO2. The extracts and fractions were solubilised in DMSO, and diluted appropriately with media so the extracts were tested at a final concentration of 1000, 10, and 1 μg/mL; 5 μL of sample was added to each well. Cells+samples were incubated (37° C., 3 hours), before the addition of calcium ionophore A23187. Following 20 min incubation, the plate was centrifuged (1000 g, 3 min) and the supernatants were removed. Included on the plate was a positive control (aspirin; 100 μM), and DMSO control, both with and without calcium ionophore A23187.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[CH2:28][CH3:29])(=O)C>C(O)CC.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:8]1[CH:29]=[CH:28][C:16]([C:2]2[N:7]=[C:6]([N:8]3[C:12]4[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[N:4][CH:3]=2)=[CH:11][CH:12]=1
Reactant: CCOC(C)=O
Reactant: Nc1ccc2ncn(-c3cncc(Cl)n3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: Nc1ccc2ncn(-c3cncc(-c4ccncc4)n3)c2c1

Procedure:
Under a nitrogen atmosphere a mixture of 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6-amine (50 mg, 0.20 mmol), 4-pyridylboronic add (30 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) in toluene-n-propanol (2 mL, 3:1) was treated with 2M aqueous sodium carbonate solution (0.14 mL, 0.84 mmol). The resulting mixture was stirred vigorously whilst being heated under reflux overnight. Upon cooling, the mixture was diluted with ethyl acetate (10 mL) and washed with H2O (1×10 mL). The aqueous phase was extracted with ethyl acetate (10 mL) and the organic layers combined and washed with 0.5M Na2CO3, brine and then dried (Na2SO4). Removal of solvent fit vacuo then yielded crude product, which was purified by column chromatography using dichloromethane-methanol (98:2-91:9) as eluent to furnish the product (32 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:17][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COC(c1ccc(N)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g), PPh3 (1.56 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (0.93 mL) slowly. The reaction was stirred at RT for 5 h and at reflux for overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken into ether. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a crude material as a very viscous brown oil which was purified by chromatography through silica gel (400 g, 2:1:7 to 3:1:6 EtOAc/Et3N/hexanes) to afford (S)-2-[1-(4-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]([CH2:35][OH:36])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:36][CH2:35][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:26]([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:15][CH2:16][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:12][CH2:13]3)[CH:18]=2)=[O:24])[CH2:27]1
Reactant: OCC1CNc2ccccc21
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CC(CO)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
85 mg (0.25 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 50 mg (0.32 mmol) (2,3-dihydro-1H-indol-3-yl)-methanol in 50 μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol) TBTU and stirred for 5 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:23]([O:25]C)=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:23]([OH:25])=[O:24])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2ccc(F)cc2)C(=O)O)cc1
Yield: 91.6 %

Procedure:
The same procedures as in Example 90 were carried out from the compound obtained in Example 40 (2.5 g), 1 mol/L of an aqueous sodium hydroxide solution (21 mL), and methanol (150 mL), to give the captioned compound (2.2 g, 90%) as crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[Mg].[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)=[O:7].[Cl-].[NH4+]>O1CCCC1>[OH:7][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(NC(C)=O)cc1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
To a stirred and refluxed Grignard complex previously prepared starting from 55.1 parts of 1-bromopropane, 10.9 parts of magnesium and tetrahydrofuran was added a solution of 25 parts of N-(4-formylphenyl)acetamide in 225 parts of dry tetrahydrofuran. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water and a saturated ammonium chloride solution. The organic layer was decanted (and set aside) and the remaining phase was extracted with ethyl acetate. The combined organic layers were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 20 parts (64.3%) of N-[4-(1-hydroxybutyl)phenyl]acetamide as a residue (interm. 7).