Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:44])[F:43])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@H:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:44])[F:43])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@H:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CCCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@H]2CCCCO2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
67 mg (0.11 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 25 mg (41% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([N:19]([CH3:35])[C:20]([NH:22][C:23]2[C:28]([Cl:29])=[C:27]([O:30][CH3:31])[CH:26]=[C:25]([O:32][CH3:33])[C:24]=2[Cl:34])=[O:21])[CH:14]=1.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C1COCC1>[Cl:34][C:24]1[C:25]([O:32][CH3:33])=[CH:26][C:27]([O:30][CH3:31])=[C:28]([Cl:29])[C:23]=1[NH:22][C:20](=[O:21])[N:19]([C:15]1[N:16]=[CH:17][N:18]=[C:13]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][N:9]([CH3:10])[CH3:11])=[CH:7][C:2]=2[NH:1][C:36](=[O:39])[CH:37]=[CH2:38])[CH:14]=1)[CH3:35]
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(CN(C)C)cc3N)ncn2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(CN(C)C)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: -10 °C
Reaction time: 5 h
Yield: 9.5 %

Procedure:
To a stirred solution of 1-[6-(2-amino-4-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-urea (45 g, 0.11 mmol) in THF (40 mL) at −10° C. was added acryloyl chloride (30 g, 0.33 mmol) in THF (3 mL). The solution was stirred at −10° C. for 5 hours. LCMS showed major product peak. The reaction was quenched with MeOH (3 mL) and evaporated. The residue was purified by prep-HPLC (water/ACN in NH4HCO3 condition) to afford the title compound (6 mg, yield: 15%). 1H-NMR (400 MHz, MeOH-d4) δ 8.25 (s, 1H), 7.47 (d, 1H), 7.44 (s, 1H), 7.16 (dd, 1H), 6.70 (s, 1H), 6.33-6.20 (m, 3H), 5.67 (dd, 1H), 3.84 (s, 6H), 3.43 (s, 2H) 3.22 (s, 3H), 2.20 (s, 6H); MS (ESI): 574 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C(N(CC)CC)C.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (42, 3.0 mL, 29.8 mmol) in tetrahydrofuran (50 mL) were added triethylamine (9.13 mL, 65.5 mmol) and propane-1-sulfonyl chloride (2.90 mL, 25.8 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the compound (72, 2.0 g, 28%) that was used in the next step.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:39])[CH:19]([C:24]1[CH:29]=[C:28](O)[CH:27]=[C:26]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=1)[CH2:20][C:21]([CH3:23])=[CH2:22].N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:39])[CH:19]([C:24]1[CH:29]=[C:28]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:27]=[C:26]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=1)[CH2:20][C:21]([CH3:23])=[CH2:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=C(C)CC(C(=O)OC)c1cc(O)cc(OCc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.7 %

Procedure:
Trifluoromethanesulfonic anhydride (3.3 mL, 10.1 mmol) was added dropwise to a stirred solution of 2-(3-benzyloxy-5-hydroxyphenyl)-4-methyl-pent-4-enoic acid methyl ester (4.5 g, 13.8 mmol) and pyridine (3.0 mL, 38.7 mmol) in DCM (80 mL) at 0° C. then warmed to room temperature. After 1 h, the mixture was washed with 1M HCl (50 mL), dried (MgSO4) and concentrated in vacuo to afford the title product as an orange oil (6.10 g, 96%). 1H-NMR (400 MHz, CDCl3): δ 7.42-7.30 (m, 5H), 6.97 (s, 1H), 6.85 (s, 1H), 6.78 (s, 1H), 5.05 (s, 3H), 4.75 (s, 1H), 4.64 (s, 1H), 3.77 (t, 1H), 3.66 (s, 3H), 2.77 (dd, 1H), 2.40 (dd, 1H), 1.69 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.Cl[C:32]1[N:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][O:11][CH2:10][C@H:9]([CH3:13])[O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=1)[O:1][C:32]1[N:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 75.8 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (200 mg, 0.464 mmol) synthesized in Example (38d) and methyl 5-chloropyrazine-2-carboxylate (120 mg, 0.695 mmol) synthesized in Example (62b) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (257 mg, 1.86 mmol) was added, followed by stirring at 80° C. for 7 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%). The resulting yellow solid was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (4 mL) was added, followed by stirring at room temperature for 1.5 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%) to afford the desired compound (164 mg, yield 93%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1C=CC=C2[C:11]=1C(O)=CC=C2.C[CH2:14][CH2:15][CH2:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)C>[CH:11]1[C:18]2[C:19]3[C:14]([CH:15]=[CH:16][C:17]=2[O:24][NH:1][CH:2]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: Nc1cccc2cccc(O)c12
Reactant: CCCCCCC(=O)CCCC
Solvent: CCO
Product: C1=Cc2c(ccc3ccccc23)ON1
Yield: 35.9 %

Procedure:
With 6.3 g of 8-amino-1-naphthol and 20 ml of ethanol, 8.1 g of 5-undecanone was mixed. The mixture was refluxed for 3 hours. The reaction mixture was condensed, and purified in a column chromatography (silica gel, n-hexane/ethyl acetate=1/6) to obtain 2.6 g of naphthooxazinine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][CH2:38][CH2:39][O:40][CH3:41])[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH2:42].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][CH2:38][CH2:39][O:40][CH3:41])[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Reactant: COCCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)CC4=O)c(OC)cc23)c2c1OCO2
Yield: 67.8 %

Procedure:
This was prepared by the method described in example 4 but using 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (140 mg, 0.38 mmol), 5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-amine (107 mg, 0.42 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 0.81 ml) in DMF (2 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (150 mg, 67%) as a pale orange solid; NMR Spectrum:(DMSOd6) 2.04 (quintet, 2H), 2.20 (s, 3H), 2.59 (t, 2H), 2.72 (t, 2H), 2.91 (s, 2H), 3.30 (s, 3H), 3.32 (t, 2H), 3.47 (t, 2H), 3.53 (t, 2H), 3.94 (s, 3H), 4.14 (t, 2H), 6.14 (s, 2H), 7.07 (s, 1H), 7.15 (s, 1H), 7.83 (s, 1H), 8.32 (s, 1H), 9.49 (s, 1H);
Reaction SMILES: CO[C:3]([O:20]C)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:35][C:36](=[NH:38])[CH3:37]>CN(C=O)C.O>[CH3:37][C:36]1[N:38]=[C:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:20])=[CH:13][CH:12]=2)[O:11][N:35]=1
Reactant: CC(=N)NO
Reactant: COC(Cc1ccc(C(=O)O)cc1)(OC)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ccc(CC(=O)c3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.9 %

Procedure:
To 4-(2,2-dimethoxy-2-phenylethyl)benzoic acid (1.1 g, 3.84 mmole) in DMF (15 mL) was added carbonyldiimidazole (0.68 g, 4.2 mmole). After 20 min, N-hydroxy ethanimidamide (0.33 g, 4.5 mmole) was added and the mixture stirred for 45 min. at r.t. followed by 100° C. overnight. The reaction was cooled, poured in H2O (30 mL) and extracted with hexane/ethylacetate 1:1. The organic phase was dried over Na2SO4 and concentrated. The residue was dissolved in 100 mL acetone and treated with p-toluene sulfonic acid (100 mg) for 2 h. Et3N (0.5 mL) was added, and the mixture was concentrated to dryness. The residue was dissolved in 2:1 hexane/ethyl acetate (10 mL) and passed through a pad of silica gel, eluting with 1: 1 hexane:EtOAc. The fractions were concentrated, and the residue was stirred with 4:1 hexane:EtOAc 10 mL to give 0.49 g of the desired compound.
Reaction SMILES: [C:1]1(=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CCO.[Pd]>[CH:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccccc1C=C1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1CC1CCCC1
Yield: 93.6 %

Procedure:
A mixture of 1-cyclopentylidenemethyl-2-methoxybenzene (408 mmol, 76.7 g) and 10% Pd on carbon (7.67 g, 10% by weight) in absolute EtOH (767 mL) was shaken at room temperature under 54 psig of hydrogen pressure for 2.5 hours. Additional H2 was added to the vessel as necessary to maintain the initial pressure. The volatiles were removed in vacuo and the residue vacuum distilled to afford the title compound as a colorless oil (72.7 g, 94%). The desired fraction comes over at 85°-95° at 2.0-2.5 mm Hg and is used as such in the subsequent transformation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH:17]([C:19]1[C:20]([CH3:35])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[CH3:18]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:17]([C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH3:18])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Reactant: CCOC(=O)CCc1ccc(O)cc1C
Product: CCOC(=O)CCc1ccc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 60B]) was reacted with [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) to give [rac]-3-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:12][CH2:13][OH:14])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCO)c(F)c1
Temperature: 150 °C
Reaction time: 10 h

Procedure:
5.00 g (35.69 mmol) of 3-fluoro-4-hydroxybenzaldehyde are dissolved in 50 ml of dry DMF. 5.35 g (42.82 mmol) of 2-bromoethanol and 19.73 g (142.74 mmol) of potassium carbonate are added. The reaction mixture is stirred at 150° C. for 10 h. The mixture is then filtered, and the filtrate is freed from the solvent on a rotary evaporator. The residue is taken up in 30 ml of ethyl acetate, and 20 ml of sat. aqueous sodium bicarbonate solution are added. The phases are separated and the organic phase is dried over magnesium sulfate. The solvent is removed on a rotary evaporator. The product obtained is used without further purification in the subsequent reaction.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4].C1C=CC(COC([NH:30][C@H:31]([C:37](OC2C=CC([N+]([O-])=O)=CC=2)=[O:38])[CH2:32][CH2:33][C:34]([NH2:36])=[O:35])=O)=CC=1>CN(C=O)C>[NH2:30][C@H:31]([C:37]([NH:1][C@H:2]([C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4])=[O:38])[CH2:32][CH2:33][C:34](=[O:35])[NH2:36]
Reactant: C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H](NC(=O)[C@@H](N)CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.36 g H-Thr-Pro-OtBu is dissolved in 10 ml DMF, after which 1.93 g Z-Gln-ONp is added and the reaction mixture is stirred for about 20 hours at room temperature. After evaporation of the mixture to dryness, the residue is dissolved in EtOAc and washed consecutively with 5% KHSO4 solution, 5% NaHCO3 solution and a saturated NaCl solution. The solution is then dried over Na2SO4 and filtered, and the filtrate is evaporated to dryness.
Reaction SMILES: [CH3:1][C:2]1(C)CC[C:9]2[C:4](=[CH:5][C:6]([C:12]#[C:13][Si](C)(C)C)=[CH:7][CH:8]=2)[S:3]1.[OH-].[K+].[CH:21](O)([CH3:23])[CH3:22]>>[CH3:22][C:21]1([CH3:23])[C:9]2[C:4](=[CH:5][C:6]([C:12]#[CH:13])=[CH:7][CH:8]=2)[S:3][CH2:2][CH2:1]1
Reactant: CC(C)O
Reactant: CC1(C)CCc2ccc(C#C[Si](C)(C)C)cc2S1
Agent: [K+]
Agent: [OH-]
Product: C#Cc1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1 g (3.6 mmol) of 4,4-dimethyl-7-trimethylsilylethynyl-thio-chroman (Compound 47) in 10 ml of isopropyl alcohol was added 5 ml of 1N KOH solution. The reaction mixture was stirred at room temperature for 18 hours and the isopropanol was then removed under vacuum. The residue was extracted with ether and the ether extracts were combined and washed with dilute HCl solution, water and saturated NaCl solution, and were thereafter dried (MgSO4). The solvent was removed in vacuo to give impure 4,4-dimethyl-7-ethynyl-thiochroman (Compound 48) as a pale yellow oil. This mixture was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:5].[C:24](O)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[C:24]([O:1][CH2:2][CH2:3][N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:5])(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCN(C)CCO
Product: CCCCCCCCCCCCCCCCCCN(C)CCOC(=O)CCCCCCCCCCCCCCCCC
Temperature: 180 °C
Yield: 96.5 %

Procedure:
A four-neck flask provided with a stirrer, a thermometer and a dehydrating tube was charged with 200 g of the N-(2-hydroxyethyl)-N-methyloctadecylamine and 174 g of octadecanoic acid. The mixture was heated to 180° C. and maintained at this temperature for 12 hours while distilling off the water thus formed. Thus 350 g of N-(2-octadecanoyloxyethyl)-N-methyloctadecylamine was obtained. Based on the NMR and IR spectra, it was confirmed that this product had the following structure. This compound will be referred to as the enhancer 25 hereinafter. ##STR31##
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Br:34]N1C(=O)CCC1=O.C(OCC)(=O)C>C(#N)C>[Br:34][C:4]1[CH:3]=[N:2][N:1]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cncc(-n2cccn2)c1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Brc1cnn(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Pyrazol-1-ylpyridine (500 mg, 3.44 mmol) was dissolved in acetonitrile (15 ml), and ammonium cerium(IV) nitrate (944 mg, 1.72 mmol) was added (slightly exothermic). N-Bromosuccinimide (736 mg, 4.13 mmol) was added in portions (slightly exothermic) and the mixture was stirred at room temperature for 30 minutes (min) and then heated under reflux for 3 hours (h). After the mixture had cooled, ethyl acetate was added. The organic phase was washed with water, washed with a sodium sulphate solution and then dried over magnesium sulphate. The solvent was removed on a rotary evaporator under reduced pressure.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17]I>C1COCC1>[CH3:17][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][C:12]1=[O:16]
Reactant: O=C1CN(Cc2ccccc2)CCN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccccc2)CC1=O

Procedure:
Sodium hydride (50% in oil, 10.4 g., 0.22 mole) is added to a stirred solution of 4-(phenylmethyl)piperazinone (Example 45, 38.0 g., 0.20 mole) in THF (2.0 l.). After 1 hour methyl iodide (80.0 g., 0.75 mole) is added and the reaction solution is refluxed for 2.5 hours. The THF is removed under reduced pressure and the residual oil is partitioned between chloroform and water. Evaporation of the chloroform gives an oil which is chromatographed on silica gel to give the title compound, which is converted to the p-TSA salt, m.p. 138°-140°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 65 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
2-Fluoro-5-nitrobenzoic acid (1.85 g) was dissolved in ethanol (30 ml). Concentrated sulfuric acid (1.0 ml) was added to the solution, and the mixture was stirred at 65° C. overnight. The solvent was removed from the reaction solution by distillation under the reduced pressure, and the residue was adjusted to pH 7 by the addition of a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure to give 1.79 g (84.3%) of ethyl 2-fluoro-5-nitrobenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.Br[CH2:22][C:23](=O)[CH3:24].C(=O)([O-])O.[Na+]>C(O)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][O:12][C:11]1[C:2]2[N:3]([CH:22]=[C:23]([CH3:24])[N:1]=2)[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=1
Reactant: COC(=O)c1cnc(N)c(OCc2ccccc2F)c1
Reactant: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(OCc2ccccc2F)c2nc(C)cn2c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a suspension of 2.15 g of methyl 6-amino-5-[(2-fluorobenzyl)oxy]nicotinate in 43 ml of ethanol was added 1.09 ml of bromoacetone, followed by stirring at 80° C. for 4 hours. To the reaction mixture was added 1.09 ml of bromoacetone, followed by stirring at 80° C. for 4 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure, followed by extracting with ethyl acetate and washing with saturated brine. After drying over anhydrous magnesium sulfate and then filtering, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.39 g of methyl 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](Cl)=[O:11].[NH:14]1[CH:18]=[CH:17]N=N1.C(=O)([O-])[O-].[K+].[K+]>C1S(=O)(=O)CCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH:17]=[CH:18][N:14]=1
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1-c1ncco1
Temperature: 140 °C
Yield: 18.8 %

Procedure:
A mixture of 2-Chlorocarbonyl-benzoic acid methyl ester (1.3 gram, 6.56 mmol), 1H-triazole (0.42 ml, 7.22 mmol) and potassium carbonate (2.78 g, 20 mmol) in 12 ml of tetramethylene sulfone was heated at 140° C for half an hour. The mixture was cooled, diluted with ethyl acetate, washed with water 5 times, and dried. After concentration the crude was purified by flash column (50% ethyl acetate in hexane) to afford 250 mg of 2-Oxazol-2-yl-benzoic acid methyl ester as a light yellow liquid. MS: (M+H)/z=204.1.