Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[NH:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CC(O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH:4]2[O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:19][CH2:18]1
Reactant: O=C1NCC(CCCl)O1
Reactant: Clc1ccccc1N1CCNCC1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CO
Product: O=C1NCC(CCN2CCN(c3ccccc3Cl)CC2)O1
Yield: 24.3 %

Procedure:
A stirred mixture of 8.3 g (0.056 mol) of 5-(2-chloroethyl)-2-oxazolidinone, 11 g (0.056 mol) of 1-(2-chlorophenyl)piperazine and 7.7 g (0.056 mol) of potassium carbonate in 150 ml of 2-propanol was heated at reflux temperature for 18 h. The mixture was filtered and the filtrate concentrated at reduced pressure. The residue was dissolved in 2-propanol and treated with a solution of 6.9 g (0.0595 mol) of maleic acid in warm methanol. The resulting maleic acid salt was collected and recrystallized several times from a 2-butanone/methanol mixture to obtain 5.8 g (25%) of solid, mp 166°-168.5° C.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH3:15])[CH:5]=1)[NH2:3].CO[CH:18](OC)[CH2:19][C:20](=O)[CH3:21]>Cl.O.CO>[CH3:15][O:14][C:6]1[CH:5]=[C:4]([N:2]2[CH:18]=[CH:19][C:20]([CH3:21])=[N:3]2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(NN)cc1OC
Reactant: COC(CC(C)=O)OC
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1OC
Temperature: 90 °C
Yield: 53.7 %

Procedure:
To a stirred solution of 4-hydrazino-2-methoxybenzoic acid, methyl ester hydrochloride (0.88 g) from Example 104 and one drop of concentrated hydrochloric acid in a 1:1 water/methanol (10 ml) mixture was added acetylacetaldehyde dimethylacetal (0.53 g). The reaction was heated to 90° C. for 5 minutes. The reaction was concentrated in vacuo and partitioned between 1 N sodium hydroxide (10 ml) and ethyl acetate (50 ml). The organic phase was removed and washed with brine, dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent in vacuo afforded a brown oil which was combined with a previous lot (0.54 g) and recrystallized three times from diisopropyl ether to give 2-methoxy4-(3-methyl-pyrazol-1-yl)-benzoic acid, methyl ester (0.5 g). m.p. 167-169° C., MS, m/z: 246 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.50 g, 45.8 mmol) in DMF (200 mL) was added potassium carbonate (6.33 g, 45.8 mmol) followed by iodomethane (3.42 mL, 55.0 mmol). The reaction was stirred under N2 at RT 3 h. The reaction was poured into 10% aqueous K2CO3 (500 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with saturated NaCl (2×150 mL), dried (MgSO4) and concentrated to give 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (11.8 g, 48.5 mmol, 106% yield) as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)#[N:2].[ClH:27]>>[ClH:27].[N+:24]([C:23]1[CH:22]=[CH:21][CH:20]=[C:4]([O:5][CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[C:3]=1[C:1]#[N:2])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc([N+](=O)[O-])c1C#N
Agent: Cl
Product: N#Cc1c(OC[C@@H]2CCCCN2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 1d from (S)-tert-butyl 2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 47e). MS 262 (MH+-HCl).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:32])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)[CH2:17][C:16](=[O:32])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M25) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (84 mg).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]([Cl:16])([Cl:15])[C:10]([N:12]=[C:13]=[O:14])=[O:11]>O.CC(C)=O>[Cl:8][C:9]([Cl:16])([Cl:15])[C:10]([NH:12][C:13](=[O:14])[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Oc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(=O)C(Cl)(Cl)Cl)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.7 g (0.05 mol) of phenol are dissolved in a mixture of 10 g of water and 10 g of acetone. 9.4 g (0.05 mol) of trichloroacetyl isocyanate are subsequently added dropwise over the course of 30 minutes. The mixture is stirred at room temperature for 30 minutes and under reflux for 2.5 hours. The solvent mixture is evaporated in a rotary evaporator, and the solid obtained is recrystallized from DMSO (dimethyl sulfoxide).
Reaction SMILES: [C:1]([C:9]1[C:10]([OH:24])=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CN(C)C=O>[C:1]([C:9]1[C:10]([O:24][CH2:31][CH3:32])=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C(c1ccccc1)c1cnc2c(cnn2Cc2ccco2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1

Procedure:
3.3 g. of 5-Benzoyl-4-hydroxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine (0.01 mol.) are dissolved in 20 ml. of dimethylformamide. 2.8 g. of potassium carbonate and 3.1 g. of ethyl iodide are added and the mixture is warmed for 12 hours at 60°. Excess potassium carbonate is filtered off and water is added. 5-Benzoyl-4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine precipitates and is recrystallized from hexane, yield 3 g. (86%), m.p. 70°.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:11])[CH3:10]>>[C:1]1([S:7][C:9]([CH3:11])([CH3:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: C=C(C)C
Product: CC(C)(C)Sc1ccccc1
Yield: 93.8 %

Procedure:
To a mixture of 55 grams (0.5 mole) of thiophenol and 51 grams of boron trifluoride-phosphoric acid complex was slowly added, with stirring and cooling, 34 grams (0.6 mole) of isobutylene at 0° C. After addition was complete the mixture was stirred at 0° C. for two hours. The organic layer was separated from the catalyst layer and added to 200 ml of toluene. The toluene layer was distilled in a one-foot packed column to give 78 grams of tert-Butyl Phenyl Sulfide, b.p. 55°/3.0 mm (yield 94%). The nmr spectrum agreed with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O.[H][H]>[O-]S([O-])(=O)=O.[Ba+2].C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C(=O)Nc1ccc(OCCc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: CN(C)C(=O)Nc1ccc(OCCc2ccccc2)c(N)c1

Procedure:
A mixture of 3-[3-nitro-4-(phenethyloxy)phenyl]-1,1-dimethylurea (5.8 g; 0.0175 mol), 5% palladium in BaSO4 catalyst (6.0 g) and 95% ethyl alcohol (100 ml) is shaken in a hydrogen atmosphere at 2.8 kg/cm2 pressure (40 psig) for 18 hours. The mixture is then filtered and the ethanol removed under vacuum. The residue is washed with toluene to afford the title compound, m.p. 125°-126° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:33][S:30]([C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([C:19]1[CH:20]=[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=[CH:17][N:18]=1)[CH2:22][CH2:23]2)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 131.3 %

Procedure:
To a solution of 4a (0.55 g) in 8 mL of DCM, was added trifluoroacetic acid (3 mL, 33 eq) at room temperature. The reaction mixture was stirred at room temperature for 3 h then the solvent and excess trifluoroacetic acid were removed under a stream of nitrogen to give 0.57 g of 4b.
Reaction SMILES: B(F)(F)F.O(CC)CC.[CH:10]1([CH:16]([OH:18])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:19][C:20]1([O:23][CH2:22]1)[CH3:21]>C1CCCCC1>[CH:10]1([CH:16]([O:18][C:20]([CH3:21])([CH3:19])[CH2:22][OH:23])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(O)C1CCCCC1
Reactant: CC1(C)CO1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(OC(C)(C)CO)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
BF3—OEt2 (2.0 ml) is added dropwise to a solution of 1-cyclohexylethanol (16.6 g, 127.0 mmol) and isobutylene oxide (2.9 g, 40.0 mmol) in cyclohexane (20 ml) that has been cooled to 0° C. The reaction mixture is now stirred at 0° C. for a further 30 minutes, and further, BF3—OEt2 (2.0 ml) is then added. After a further 3 hours at 0° C., the cooling is removed and the reaction solution is washed once with 1 M NaOH (15 ml). The organic phase is dried over Na2SO4, filtered off and freed from solvent in a rotary evaporator. The 1-cyclohexylethanol that has not completely reacted is removed from the crude product; thus, obtained by means of bulb tube distillation (BTD) and 5.3 g crude 2-(1-cyclohexylethoxy)-2-methyl-1-propanol is obtained which has a GC content of 75% and can be used in the next reaction without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:13][CH:14]=2)O1.Br[C:21]1[N:26]=[C:25]2[S:27][C:28]([NH:30][C:31](=[O:43])[C:32]3[CH:37]=[CH:36][C:35]([C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[CH:34][CH:33]=3)=[N:29][C:24]2=[CH:23][CH:22]=1>>[C:16]([NH:15][C:12]1[N:13]=[CH:14][C:9]([C:21]2[N:26]=[C:25]3[S:27][C:28]([NH:30][C:31](=[O:43])[C:32]4[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:42])[CH2:39][OH:40])=[CH:34][CH:33]=4)=[N:29][C:24]3=[CH:23][CH:22]=2)=[CH:10][CH:11]=1)(=[O:18])[CH3:17]
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(=O)Nc1ccc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)CO)cc4)sc3n2)cn1
Yield: 14 %

Procedure:
The titled compound (yield=14%, white solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide and 2F (Example 2) were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.14 (s, 3H) 3.49 (d, J=5.31 Hz, 2H) 4.78 (t, J=5.31 Hz, 1H) 7.58 (d, J=8.59 Hz, 2H) 8.06-8.18 (m, 3H) 8.18-8.26 (m, 2H) 8.52 (dd, J=8.84, 2.53 Hz, 1H) 9.09 (d, J=1.77 Hz, 1H) 10.73 (s, 1H) 13.00 (s, 1H); ESI-MS: m/z 462.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.CN(CCN(C)C)C.[CH2:20]([O:22]CC)C.[Li]CCCC.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH:20]=[O:22])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCOCC
Reactant: COc1cc(Cl)cc(OC)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(OC)c1C=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 33.9 %

Procedure:
A solution of 1-chloro-3,5-dimethoxybenzene (5 g, 29.0 mmol) and TMEDA (4.37 mL, 29.0 mmol) in diethyl ether (100 mL, 962 mmol) at −78° C. under N2 atmosphere was charged with BuLi (19.91 mL, 31.9 mmol) dropwise over a period of 30 minutes using a syringe pump. After stirring for 4 hours at −78° C., DMF was added and the reaction mixture continued to stir for 1.5 hours after which 1N HCl (˜30 mL) was added (all at −78° C.). The reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by ISCO using hexanes/EtOAc as eluent. Fractions containing the desired product were concentrated to dryness to give the title material (1.97 g, 9.82 mmol, 33.9% yield) as a light yellow solid. LC (Method B): 1.924 min. LCMS (APCI) calcd for C9H10ClO3 [M+H]+ m/z 201.03. found 201.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 10.28 (s, 1H), 6.87 (s, 2H), 3.86 (s, 6H).
Reaction SMILES: [O:1]=[C:2]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12].[OH-].[Li+]>C1COCC1.O>[O:1]=[C:2]([NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccccc1COc1cccc(CC(=O)NCc2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1cccc(OCc2ccccc2C(=O)O)c1)NCc1ccc(C(F)(F)F)cc1
Reaction time: 168 h
Yield: 25.1 %

Procedure:
Methyl 2-{[3-(2-oxo-2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]methyl}-benzoate (82 mg, 0.18 mmol) in THF (2 ml) was cooled in an ice-bath. Lithium hydroxide (8.6 mg, 0.36 mmol) in water (1 ml) was dropped in. The cooling-bath was then removed and the mixture was stirred for 7 days and then evaporated in vacuum to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜3, and extracted with ethyl acetate. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM and MeOH/DCM (1:99, then 2:98) as eluant gave 20 mg the desired product, yield 22.5% (two steps).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:27])=[C:24]([C:37]([OH:40])([CH3:39])[CH3:38])[N:23]=[C:22]2[CH2:41][CH2:42][CH3:43])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:27])=[C:24]([C:37]([OH:40])([CH3:39])[CH3:38])[N:23]=[C:22]2[CH2:41][CH2:42][CH3:43])=[CH:18][CH:19]=1)([OH:7])=[O:5]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.1 %

Procedure:
A mixture of 6.6 g of pivaloyloxymethyl 1-[(2'-t-butoxycarbonylbiphenyl -4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in step (c) above] and 57 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was triturated with ethyl acetate to crystallize it, giving 6.52 g of the title compound as the hydrochloride, melting at 170°-173° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH3:19][N:20]([CH3:33])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][O:31][CH3:32])[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1>[CH3:33][N:20]([CH3:19])[C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:25])[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][O:31][CH3:32]
Reactant: Brc1ccccn1
Reactant: COCOc1ccc(C=O)cc1N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C(O)c2ccccn2)cc1N(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromopyridine (3.05 g, 19.3 mmol) in dry tetrahydrofuran (100 ml) was added dropwise n-butyl lithium in hexane (1.6M, 12.0 ml, 19.2 mmol) under nitrogen atmosphere. After stirring at -78° C. for 30 minutes, thereto was added dropwise a solution of the aldehyde compound (Compound A) (3.00 g, 14.3 mmol) in dry tetrahydrofuran (20 ml), and the mixture was stirred at -78° C. for 2 hours. A saturated aqueous solution of ammonium chloride (10 ml) was added thereto, and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (200 ml) and extracted with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([CH3:26])[C:16]([O:22]C(=O)C)=[CH:17][CH:18]=3)[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N1C=CN=C1.O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([CH3:26])[C:16]([OH:22])=[CH:17][CH:18]=3)[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2COc3c(ccc(OC(C)=O)c3C)C2=O)cc1OC
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: O
Product: COc1ccc(C2COc3c(ccc(O)c3C)C2=O)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetic acid 3-(3,4-dimethoxy-phenyl)-8-methyl-4-oxo-chroman-7-yl ester (1.1 g, 3.2 mmol) and imidazole (3.2 g, 47 mmol) were refluxed in EtOH (100 ml). The reaction was complete after 90 minutes and allowed to cool to room temperature before pouring into stirred H2O (800 ml). A fine white precipitate was filtered off and 1H NMR in d-CDCl3 indicated the solid was 3-(3,4-Dimethoxy-phenyl)-7-hydroxy-8-methyl-chroman-4-one in >95% purity (0.31 g, 30%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:30])[C:17](=[CH:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[C:18]([CH3:20])=O)[CH3:14]>>[CH2:13]([O:15][C:16]([C:17]1[CH:21]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[CH3:29])[C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][NH:9][C:10]=2[NH:12][C:18]=1[CH3:20])=[O:30])[CH3:14]
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: CCOC(=O)C(=Cc1cc(C)ccc1C)C(C)=O
Product: CCOC(=O)C1=C(C)Nc2[nH]nc(-c3ccccc3)c2C1c1cc(C)ccc1C

Procedure:
Starting from 3-phenyl-5-(1H)pyrazolamine and ethyl-2-(2,5-dimethylbenzyliden)acetoacetate.
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:2][CH2:3][CH3:4].[OH:19]OS([O-])=O.[K+].C([O-])(O)=O.[Na+].CO>O>[CH2:1]([C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N+:12]([O-:19])=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c2c(nc3c1CCCC3)CCCC2
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1c2c([n+]([O-])c3c1CCCC3)CCCC2
Reaction time: 24 h
Yield: 125.3 %

Procedure:
Into a 2 L round-bottomed flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen inlet are placed 38.0 g (0.16 mol) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine, 72.0 g (0.12 mol) of Oxone (Note 9), 28.5 g (0.34 mol) of NaHCO3, 790 mL of methanol and 240 mL of water. The resulting suspension is stirred at 45°-50° C. in an atmosphere of nitrogen for 24 hrs. (Note 10). The cooled reaction mixture is vacuum filtered, washing the residual salts with methanol (2×50 mL). The methanol is removed from the combined filtrates by means of a rotary evaporator and the resulting mixture is extracted with methylene chloride (3×100 mL). The combined extracts are washed with water (2×50 mL), dried using anhydrous magnesium sulfate and concentrated to dryness by means of a rotary evaporator. Residual solvent is removed at 0.1 mm, yielding 39 g (96%) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine-N-oxide as a pale yellow solid, mp 89°-92° C. (Note 11).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:8]([F:18])[CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>>[C:20]1(=[O:30])[N:24]([CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[C:8]([F:18])[CH:7]=2)[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O[C@@H](CCl)CNc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2)c(F)c1

Procedure:
N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline is reacted with potassium phthalimide to provide N-[3-pthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholinyl)aniline (Formula IV, R1═R3 is H; X is O; one R2 is H and the other R2 is F; and n is 1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:12])[CH3:11]
Reactant: CC(=O)c1ccccc1OC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccccc1OC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 1-(2-Trifluoromethoxyphenyl)ethanone (1.00 g, 4.90 mmol) in THF (5 mL) at 0° C. was added 1M LiAlH4 in THF (5.9 mL, 5.9 mmol), and the solution was allowed to warm to rt. A few drops of water were added to quench. The mixture was concentrated in vacuo, transferred to a separatory funnel, and extracted using DCM and sat. aq. Rochelle salt. The organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[C:19]2[NH:20][C:21]3[C:22]([N:27]=2)=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.C(=O)([O-])[O-:31].[K+].[K+]>C(O)(=O)C.O>[C:1]1([S:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[C:19]2[NH:20][C:21]3[C:22]([N:27]=2)=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCSc2ccccc2)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCS(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.8 gm (0.0074 mol) of 2-[2-(2-phenylthioethoxy)-4-methoxyphenyl]imidazo[4,5-b]pyridine in 40 ml of glacial acetic acid was admixed with 0.84 gm of hydrogen peroxide (30%), and the mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was diluted with 20 ml of water, neutralized with potassium carbonate, extracted three times with 50 ml each of methylene chloride, and dried over magnesium sulfate. The purification was carried out on 70 gm of silicagel with methylene chloride/acetone (100:0 to 80:20).