Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@H:24]([CH3:25])[C@H:23]([OH:26])[CH2:22][C@H:21]([C:27]([O:29][CH3:30])=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:1]([O:18][C@@H:19]1[C@@H:24]([CH3:25])[C@H:23]([O:26][S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:22][C@@H:21]([C:27]([O:29][CH3:30])=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)[C@@H](C)[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](C)[C@H](OS(=O)(=O)c2ccc(C)cc2)C1

Procedure:
To a mixture of 2.2.c (R=Me, P=TBDMS, A=COOCH3) (279 mg, 0.828 mmol), p-toluenesulfonyl chloride (323 mg, 1.69 mmol, 98%), DMAP (5.1 mg, 0.042 mmol) in 10 ml of dry CH2Cl2 at 0° C. (ice bath) was added Et3N (308 μL, 2.54 mmol). The mixture was refluxed for three days; then p-toluenesulfonyl chloride (320 mg, 1.69 mmol, 98%), DMAP (5.1 mg, 0.042 mmol) and Et3N (500 μL) were added. The resulting solution was refluxed for two days, p-toluenesulfonyl chloride (320 mg, 1.69 mmol, 98%), DMAP (5.1 mg, 0.042 mmol) and Et3N (500 μL) were added again and reflux was continued for another day. The resulting mixture was diluted with 20 ml of CH2Cl2, washed with brine and the aqueous phase was extracted with EtOAc (4×50 ml). The combined organic phases were dried over MgSO4. Filtration of the solvent, concentration and flash chromatography on silica (isooctane/EtOAc: 9:1), afforded 2.3.c (R=Me, P=TBDPS, L=OTos, A=COOCH3) (316 mg, 83.5%) as a light yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[Na+].Cl>>[O:1]=[C:2]1[C:10](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)CCc1ccccc1/C=C1/C(=O)Nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccccc1C=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
To 300 mg of ethyl (E)-3-[(2-oxo-1,2-dihydroindol-3-ylidenemethyl)phenyl]-propionate in 3 mL of ethanaol was added 2 mL of 2N sodium hydroxide. The mixture was stirred at 90° C. for 2 hrs, cooled and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration and washed with cold ethanol to give 30 mg of 3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-phenyl]-propionic acid as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[Cl:12][C:13]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:14]=1[O:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][C:24](OCC)=[O:25])=[CH:18][CH:17]=1>O>[Cl:12][C:13]1[CH:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=[CH:34][C:14]=1[O:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][CH2:24][OH:25])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
To a mixture of lithium aluminum hydride (200 mg) and anhydrous ether (5 ml.) is added dropwise at 0°, a mixture of ethyl 4[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate (400 mg) and ether (5 ml.). After addition is complete, the mixture is stirred for about minutes. Wet ether and water is added to destroy excess hydride. Filtration and evaporation of filtrate gives 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-penten-1-ol.
Reaction SMILES: [F:1][C:2]([F:41])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:34][CH:35]([OH:40])[C:36]([F:39])([F:38])[F:37])[C:15]2[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=2)[O:18][CH2:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25]CC)=[O:24])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[OH-].[Li+].Cl>O.O1CCCC1>[F:1][C:2]([F:41])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:34][CH:35]([OH:40])[C:36]([F:37])([F:38])[F:39])[C:15]2[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=2)[O:18][CH2:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([OH:25])=[O:24])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: CCOC(=O)c1cccc(COc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(COc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)c1
Yield: 24.9 %

Procedure:
EX-435A) A solution of ethyl 3-[[3-[[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]methyl]benzoate (22.1 mg, 0.04 mmol) and lithium hydroxide (5 mg, 0.12 mmol) in water (1 mL) and tetrahydrofuran (0.5 mL) was heated at 80° C. for 16 h. The reaction mixture was added to 6 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 5.6 mg (19%) of the desired benzoic acid product as a brown oil. HRMS calcd. for C26H23F7NO5:562.1464 [M+H]+, found: 562.1418. 1H NMR (acetone-d6) δ 3.64 (dd, 1H), 3.95 (m, 1H), 4.45-4.50 (m, 1H), 4.80 (s, 2H), 5.12 (s, 2H), 6.27-6.63 (m, 4H), 7.06-7.27 (m, 4H), 7.41 (t, 1H), 7.50 (t, 1H), 7.66 (d, 1H), 7.99 (d, 1H), 8.10 (s 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:36][CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[O:38][C:34]([CH3:33])=[CH:35][N:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cnc(C2(N)CC2)o1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)o5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methyloxazol-2-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Combiflash column chromatography (4 g flash column, CV 4.8 ml, 18 ml/min, max pressure 200 psi) using 0.5% Methanol/DCM. Yield: 0.030 g (11.76%). 1H NMR (400 MHz, CD3OD): δ 1.43-1.46 (m, 2H), 1.61-1.65 (m, 2H), 2.29 (d, 3H, J=0.8 Hz), 2.37 (s, 3H), 2.96 (s, 3H), 4.06 (s, 3H), 6.69 (s, 1H,), 7.14 (s, 1H), 7.28 (apparent t, 2H), 7.34 (dd, 1H, J=1.6, 8.4 Hz), 7.59 (d, 1H, J=1.2 Hz), 7.64 (d, 1H, J=8.4 Hz), 7.88 (s, 1H), 7.96-8.00 (m, 2H). LCMS: (ES+) m/z=554.2 (M+H)+
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:23]([CH3:22])[CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: Cc1ccc(CCBr)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1C
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.5 g--see Preparation 8), 3,4-dimethylphenethyl bromide (0.4 g--see Preparation 18), anhydrous potassium carbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 2 hours. On cooling to room temperature, water (80 ml) was added and the mixture was extracted with dichloromethane (3×70 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a yellow oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield, 0.22 g.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Cl.O>CS(C)=O>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1c(Cl)cccc1Cl
Reaction time: 1.7 h
Yield: 21 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 48.9 g (0.25 mole) of 2,6-dichlorobenzyl chloride. The reaction mixture was heated to 105° over 0.3 hours, held at 105° for 1.7 hours and poured into 1.5 l of water all with rapid stirring. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure leaving %) 48 g (79(of a light yellow viscous oil. The crude product was crystallized using 125 ml of ether, filtered, air dried and dried to a constant weight at 60° to give 13 g (21%) of a white solid m.p. 156°-158°.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[CH3:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:15]([OH:20])([CH3:14])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:9]=1
Reactant: CCCCC(C)=O
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(C)(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
n-BuLi (2.5 M in hexanes, 17.0 mL, 42.5 mmol) was added dropwise to a solution of 1,4-dibromobenzene (10.04 g, 42.5 mmol) in THF (100 mL) at −78° C. under nitrogen. After stirring at −78° C. for 1 hour, 2-hexanone (4.5 g, 44.9 mmol) was added dropwise, and the solution was warmed to room temperature and stirred overnight. The reaction mixture was quenched with water and the organic layer was separated. Next, the organic phase was washed with water, dried over Na2SO4, and concentrated on a rotary evaporator to give a crude oil. The crude was purified by column chromatography (silica gel, chloroform) to give 6 as a colorless oil (10.0 g, 91% yield). 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 1.79-1.75 (m, 2H), 1.68 (s, 1H), 1.54 (s, 3H), 1.24-1.28 (m, 4H), 0.85 (t, 3H).
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[C:41]([CH2:45][NH2:46])[CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:46][CH2:45][C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([C:36]2[CH:37]=[CH:38][C:33]([O:32][C:31]([F:30])([F:47])[F:48])=[CH:34][CH:35]=2)[CH:40]=1)=[O:7])[CH3:2]
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cccc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
A solution of acid 4B (0.35 g, 1.28 mmol) in THF (25 mL) was added with DEPC (0.25 mL, 1.3 mol eq) and the mixture was stirred at room temperature for 10′. Then [3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.376 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water (40 mL) was added to the residue that is extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organic phase was anydrified over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a white solid (0.15 g) after recrystallization from ethyl ether. Yield=24%, 1HNMR (DMSO, 200 MHz) δ 1.08 (t, 3H, J=8), 3.37 (q, 2H, J=7.5), 4.44 (d, 2H, J06.1), 5.16 (s, 1H), 6.09 (s, 1H), 7.32 (d, 1H), 7.46 (m, 5H), 7.53 (d, 1H), 7.62 (s, 1H), 7.76 (dd, 2H), 7.86 (m, 2H), 8.78 (t, 1H); [M+1] 522.51 (C25H22F4N2O4S requires 522.12).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:21])[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:5]=1.[OH-].[Na+]>CO>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][NH:11][C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:22])=[O:2])=[O:21]
Reactant: COC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(C(=O)NCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of (18(b)) (3.85 g, 11.4 mmol) in MeOH (100 mL) at room temperature under argon was treated with 2N NaOH (12 mL, 24 mmol). The reaction mixture was allowed to stir at room temperature for 4 h, concentrated to 1/5 volume and acidified to pH4 with 2N HCl. The resulting precipitate was then collected by filtration, washed with water (2×25 mL) and dried under high vacuum to yield 3-(3,4-dichlorobenzyl-carbamoyl)-benzoic acid (18(c)) as a white powder: 2.9 g (79%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[C:30](Cl)=[O:31])[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:29]=3[N:20]=[CH:21][CH:22]=[CH:23]4)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cccc2cccnc12
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc2cccnc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-8-carbonyl chloride were combined to provide N8-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-8-quinolinecarboxamide as a tan powder, m.p. 91.0-93.0° C. 1H NMR (300 MHz, DMSO-d6) δ 10.80 (t, J=5.5 Hz, 1H), 8.79 (dd, J=4.3, 1.8 Hz, 1H), 8.55-8.49 (m, 2H), 8.24 (s, 1H), 8.17 (dd, J=8.1, 1.5 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.63-7.59 (m, 2H), 7.40 (dt J=7.1, 1.2 Hz, 1H), 7.14 (dt, J=7.1, 1.2 Hz, 1H), 6.57 (broad s, 2H), 4.68 (t, J=7.0 Hz, 2H), 3.51 (m, 2H), 2.02 (m, 2H), 1.69 (m, 2H); MS (EI) m/e 410.1858 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](OC)=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:25])[NH2:30])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C#N)c1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 49 %

Procedure:
A solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (114 mg, 0.32 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 7 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 40 mg (49%) of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.7 (d, 1H, J=8 Hz), 7.6 (s, 1H), 7.5-7.4 (m, 3H), 7.3 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.75 (s, 2H). IR (KBr, cm−1) 3430, 3347, 2231, 1628, and 1601. MS (ES) m/e 340, 342.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:15])[CH:9]=1)[CH3:4].FC(F)(F)S(O[CH2:23][CH:24]([F:26])[F:25])(=O)=O>C1COCC1>[CH2:3]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:23][CH:24]([F:26])[F:25])=[C:10]([Br:15])[CH:9]=1)[CH3:4]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OCC(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride 60% dispersion in mineral oil (80 mg, 2.0 mmol, 1.0 eq.) was added portionwise to an ice-cooled solution of (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (564 mg, 2.0 mmol, 1.0 eq.) in THF (9.4 mL). The ice bath was removed and the mixture was allowed to warm to r.t. and stirred for 30 min. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (961 mg, 4.4 mmol, 2.2 eq.) in THF (1 mL) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was taken up in DCM and water was added. The layers were separated and the aq. phase was extracted with DCM (3×). The comb. org. layers were washed with sat. aq. NaCl soln., dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow oil. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:21]=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].[OH-].[Li+].Cl>CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:21]=[C:20]([C:30]([OH:32])=[O:31])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCOCC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(N4CCOCC4)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Methyl 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-morpholin-4-ylpyrimidine-4-carboxylate (Example 9, 224 mg, 0.45 mmol) was dissolved in MeOH (5 ml). 2 N lithium hydroxide (2 ml) was added and the reaction was stirred at room temperature for 3 h. The mixture was acidified with 1 N HCl and was extracted with EtOAc (3×50 ml), dried over Na2SO4 and concentrated in vacuo to provide 200 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:56][Si:57]([CH3:62])([CH3:61])[CH2:58][CH2:59]O>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([O:22][CH2:59][CH2:58][Si:57]([CH3:62])([CH3:61])[CH3:56])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COC(=O)CCC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: C[Si](C)(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester (222 mg, 0.66 mmol), triphenylphosphine (260 mg, 0.996 mmol), and diethyl azodicarboxylate (173 mg, 0.996 mmol) in THF (3 mL) at 0° C. was added a solution of 2-trimethylsilylethanol (142 μL, 0.996 mmol) in THF (3 mL). The resulting yellow solution was allowed to warm to room temperature and stirred overnight. The reaction was concentrated to dryness and ether and hexanes were added. Triphenyiphosphine oxide was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to provide 248 mg of the desired product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.18-1.30 (m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m, 2H), 2.37-2.45 (m, 2H), 3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25-4.35 (m, 2H), 5.13 (s, 2H), 5.12-5.22 (m, 1H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[N:9]1[CH:14]=[CH:13][C:12](C=O)=[CH:11][CH:10]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[Cl-].[Na+].O>[N:2]1[CH:3]=[CH:4][C:5](=[C:4]2[C:5](=[O:8])[C:6](=[C:12]3[CH:11]=[CH:10][N:9]=[CH:14][CH2:13]3)[CH2:7][N:2]([CH3:1])[CH2:3]2)[CH2:6][CH:7]=1
Reactant: CN1CCC(=O)CC1
Reactant: O=Cc1ccncc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN1CC(=C2C=CN=CC2)C(=O)C(=C2C=CN=CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 182 %

Procedure:
To a solution of 1.0 g (8.84 mmol) of 1-methylpiperidine-4-one and 1.89 g (16.70 mmol) of 4-pyridine carboxaldehyde in 88 mL of a 0.25M solution of aqueous NaOH (22.09 mmol) was added 1.16 mL (0.88 mmol) of a 25% w/w aqueous solution of cetyltrimethylammonium chloride. The mixture was allowed to stir vigorously at room temperature for 3 hours, diluted with 100 ml of brine and extracted with two 60 mL portions of methylene chloride. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to give 2.15 g (84%) of a yellow-orange powder.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]([O:18]CC)=[O:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH3:21][O-:22].[Na+].Cl>O>[CH3:21][O:22][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2
Reactant: CCOC(=O)c1nc2cc(OC)c(OC)cc2nc1Cl
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2nc(OC)c(C(=O)O)nc2cc1OC

Procedure:
3-Chloro-6,7-dimethoxy-2-quinoxalinecarboxylic acid, ethyl ester (3.5 g) was added to sodium methoxide (prepared from sodium (0.7 g) in methanol (250 ml)). The solution was heated under reflux for 2 hours. Water (50 ml) was added and the solution was heated under reflux for 45 minutes and cooled. 2N Hydrochloric acid was added to give a mixture of pH1 and the methanol was distilled off. Water (500 ml) was added and the solution was extracted with ethyl acetate. The extract was dried over magnesium sulphate, filtered and evaporated and the residue was crystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80°). The product had m.p. 163°-164° (d) (54%).