Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[CH:4]N(C)C.C(O)(=O)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[NH:30])=[CH:27][CH:26]=1.C[O-].[Na+]>CO>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]2[N:31]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[C:3]([S:2][CH3:1])=[CH:4][N:30]=2)=[CH:27][CH:26]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CSC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CSc1cnc(-c2ccc(Cl)cc2)nc1-c1cccc(C(F)(F)F)c1
Yield: 67.8 %

Procedure:
2.8 g of 1-methylmercapto-1-(3-trifluoromethylbenzoyl)-2-(N,N-dimethylamino)ethene, 2.3 g of 4-chlorobenzamidine acetate and 650 mg of sodium methoxide were added to 200 ml of methanol and the resulting mixture was allowed to react under reflux for 5 hours. After completion of the reaction, the solvent was distilled away under reduced pressure. After adding water, the residue was extracted with ethyl acetate and subjected to column chromatography. Thus 2.5 g of 2-(4-chlorophenyl)-4-(3-trifluoromethylphenyl)-5-methylmercaptopyrimidine was obtained (Compound 150).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:2][C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(C)ccn1
Product: Cc1ccnc(C(=O)C=CN(C)C)c1

Procedure:
A suspension of 2-acetyl-4-methylpyridine (0.65 g) in N,N-dimethylformamide dimethyl acetal (4 ml) was refluxed for 10 hours and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried under reduced pressure to give 3-dimethylamino-1-(4-methylpyridin-2-yl)prop-2-en-1-one (777 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]=[C:42]([C:44]3[C:48]([CH2:49][CH2:50][CH3:51])=[C:47]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:46][N:45]=3)[O:41][N:40]=2)=[CH:35][CH:34]=1)[OH:32].CCN(C(N1N=NN(C2C(Cl)=CC=CC=2)C1=O)=O)C1CCCCC1>CS(C)=O.CO>[OH:32][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]=[C:42]([C:44]3[C:48]([CH2:49][CH2:50][CH3:51])=[C:47]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[O:46][N:45]=3)[O:41][N:40]=2)=[CH:35][CH:34]=1)[CH2:30][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: O=C(O)CC1CCCNC1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN(C(=O)n1nnn(-c2ccccc2Cl)c1=O)C1CCCCC1
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCC(CC(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(piperidin-3-yl)acetic acid (51 mg, 0.36 mmol) in 0.5 mL dry DMSO was added tetrabutylammonium hydroxide (0.360 mL, 360 μmol, 1M in THF) and the reaction mixture was stirred at room temperature for 15 min. 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) was dissolved in 0.5 mL DMSO and added and the reaction mixture was agitated at 400 rpm on an INNOVA® platform shaker at 80° C. for 1.5 hours. The reaction was diluted with 250 μL of MeOH and purified by HPLC (MeOH—H2O-TFA) to give 2-(1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid. MS (m+1)=517. HPLC RT=2.08 min using a Waters Masslynx instrument equipped with a 19×100 mm 5 uM C18 column and a method of 0-100% B solvent over 15 min at a flow rate of 20 mL/min. Solvent A is 5:95 acetonitrile/water; solvent B is 95:5 acetonitrile/water and both contain 0.5% TFA.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
20.1 g (0.1 mol) of 4-chloro-3-nitro-benzoic acid, 11 ml thionyl chloride and 1 drop of dimethylformamide are mixed together and refluxed for two hours. The thionyl chloride is evaporated off.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36](Cl)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:20]=[C:21]([F:28])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:28][C:21]1[CH:20]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:18]=[C:17]([F:16])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: COc1cc(B(O)O)cc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc(C(F)(F)F)c1
Yield: 22.2 %

Procedure:
3-Methoxy-5-trifluoromethylbenzeneboronic acid (34 mg, 0.16 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (30 mg, 0.078 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (30 mg, 0.25 mmol) as described above to give the title compound (9 mg, 22%) after purification by flash chromatography on silica gel (% EtOAc in hexane=12%˜100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[Li]CCCC.[C@@H:21]12[C:30](=[O:31])[O:29][C:27](=[O:28])[C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.[Cl-].[NH4+]>C1COCC1.O>[CH:11]1([O:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[C:30]([C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[C:27]([OH:29])=[O:28])=[O:31])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)[C@H]2CCCC[C@H]2C(=O)O)cc1OC1CCCC1
Temperature: -90 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
4-Bromo-2-cyclopentyloxy-1-methoxybenzene (16.3 g, 60 mmol) was dissolved in THF (200 ml) and cooled with an ethanol/N2 bath to -90° C. BuLi (41 ml, 66 mmol) was added dropwise while keeping the temperature below -80° C. and stirred for another 15 min after the last addition. This mixture was then quickly added under a nitrogen atmosphere to a cooled solution (-90° C.) of cis-1,2-cyclohexanedicarboxylic anhydride (11.1 g, 72 mmol) in THF (200 ml). After stirring for 2 h at -80° C. solid ammoniumchloride was added and the reaction mixture was allowed to warm slowly to room temperature. Water (300 ml) was added and the anorganic layer was washed with ethyl acetate (200 ml). The combined organic extracts were washed with water (300 ml) and brine (2×300 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane and purified by chromatography (petroleum ether (60°-95° C.)/ethyl acetate: 7/13) and crystallized from petroleum ether (60°-95° C.)/ethyl acetate to give the title compound (10.1 g) as a white solid. M.p. 120°-121° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=O.O>CCCCCC.O1CCCC1>[Br:29][C:30]1[CH:31]=[C:32]([CH:33]=[C:2]([CH3:3])[CH3:1])[CH:35]=[CH:36][C:37]=1[O:38][C:39]([F:42])([F:41])[F:40]
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)=Cc1ccc(OC(F)(F)F)c(Br)c1
Yield: 56.5 %

Procedure:
150 ml of 20% strength solution of n-butyl-lithium in n-hexane were added dropwise to a suspension of 129.6 g (0.3 mol) of dry isopropyl-triphenylphosphonium iodide in 500 ml of anhydrous tetrahydrofuran, under nitrogen at 0° C. and while stirring. The deep red solution thus obtained was stirred for a further 15 minutes at 0° C., and 80.7 g (0.3 mol) of 3-bromo-4-trifluoromethoxybenzaldehyde were then added dropwise at 0° to 10° C. The mixture was then stirred at room temperature until decolorization occurred (approximately 12 hours). 900 ml of water were then added to the reaction mixture, and the mixture was extracted with 5 times 200 ml of petroleum ether. The petroleum ether phases were dried over magnesium sulphate, and the solvent was then stripped off in a rotary evaporator, in the vacuum from a water jet. 150 ml of n-hexane were added to the residue, and the mixture was stirred thoroughly and then filtered. The solvent was then distilled off from the filtrate under normal pressure, and the oily residue was then distilled in vacuo. 50 g (56.5% of theory) of 1-(3-bromo-4-trifluoromethoxyphenyl)-2-methyl-prop-1-ene were obtained as a slightly yellowish liquid of boiling point 107° to 108° C./10 mm Hg.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][C:17]#[N:18])=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH2:16][C:17]#[N:18])[CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CC#N)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1cc(Cl)cc2cc(C(=O)O)[nH]c12
Temperature: 40 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a solution of 81 mg (0.3 mmol) of 5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester in THF/EtOH/H2O (5 ml) at RT was added 39 mg of LiOH.H2O. The reaction mixture was stirred at 40° C. for three hours and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 71 mg (98%) of 5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 232.9 (M−H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=CC=1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>O>[Cl:14][CH2:15][C:16]([CH:10]1[CH2:11][CH2:12][CH2:7][CH2:13]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(CCl)C1CCCC1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a cold (˜0° C.) solution of K2CO3 (31.2 g, 225 mmol, ) in water (125 mL) was added N, O-dimethylhydroxylamine hydrochloride (10 g, 100 mmol) and toluene (125 mL). The reaction mixture was further cooled to −5° C. and chloroacetyl chloride (10 mL, 125 mmol, )was added slowly under vigorous agitation. The reaction mixture was then warmed to ambient temperature over 45 min and analyzed by GC for completion. The layers were separated and the aqueous layer was extracted with toluene (3×50 mL). The combined organic layers were concentrated to a solid residue. The residue was dissolved in anhydrous THF (200 mL) cooled to ˜0° C. To the reaction mixture was then added a solution of the cyclopentylmagnesium chloride (60 mL, 2M in diethyl ether), drop-wise, maintaining the temperature at less than about 5° C. The resulting solution was then warmed to ambient temperature over a period of ˜1 hr and then slowly quenched into a cold 3N HCl (100 mL, ). The resulting mixture was then aged for ˜30 min. The layers were separated and the aqueous layer extracted with MTBE (50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated to dryness to yield the title compound as a crude product, as a yellow liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O>CS(C)=O.O>[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:17][C:16]1[CH:18]=[CH:19][C:11]([CH:10]=[O:9])=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCOc1ccc(C=O)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
41.45 g (300 mmol) of potassium carbonate and 27.4 g (165 mmol) of potassium iodide are added to a solution of 22.8 g (150 mmol) of vanillin and 30.7 g (225 mmol) of 6-chlorohexanol in 500 ml of dimethyl sulphoxide (DMSO) and the mixture is stirred overnight at 60° C. under nitiogen. The mixture is then cooled to room temperature, poured into 600 ml of water and extracted three times with 150 ml of ethyl acetate each time. The combined organic phases are washed twice with 200 ml of water each time, dried over magnesium sulphate, filtered and concentrated. Purification of the residue by chromatography on 400 g of silica gel using cyclohexane/ethyl acetate 1:1 yields 29.95 g of 4-(6-hexyloxy)-3-methoxybenzaldehyde.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[C:9]([CH2:11][O:12][C:13]([C:15]2[N:16]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:17](=[O:32])[C:18]3[C:23]([C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:21]([Br:31])=[CH:20][CH:19]=3)=[O:14])[CH:8]=[CH:7][N:6]=1)([OH:4])=[O:3].S(=O)(=O)(O)O.[CH3:45]O>>[CH3:45][O:3][C:2]([C:5]1[CH:10]=[C:9]([CH2:11][O:12][C:13]([C:15]2[N:16]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:17](=[O:32])[C:18]3[C:23]([C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:21]([Br:31])=[CH:20][CH:19]=3)=[O:14])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C(O)c1cc(COC(=O)c2c(-c3ccccc3)c3cc(Br)ccc3c(=O)n2Cc2ccccc2)ccn1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(COC(=O)c2c(-c3ccccc3)c3cc(Br)ccc3c(=O)n2Cc2ccccc2)ccn1

Procedure:
To a solution (3.0 ml) of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid 2-carboxypyridin-4-ylmethyl ester hydrochloride (120 mg) in methanol was added conc. sulfuric acid (0.3 ml) at 0° C. with stirring, and the mixture was stirred at 50° C. for 48 hrs. After cooling the mixture, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=4/1-1/1) to give the title compound (73 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]C(=O)C)=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(NC(C)=O)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cl)c(N)c1OC
Yield: 99.4 %

Procedure:
A solution of intermediate (2-a) (0.59 mol) in hydrochloric acid (20%) (1500 ml) was stirred and refluxed for 2 hours. The mixture was cooled, alkalized with NaOH 50% and extracted twice with DCM. The combined organic layers were washed with water, dried, filtered, and the solvent was evaporated. The product was used in the next reaction step without further purification, yielding 110 g (100%) of 6-chloro-2,3-di-methoxybenzenamine (interm. 2-b)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)CCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of 4-(4-fluorophenyl)-butyric acid (6.7 g) in chloroform (15 ml) at 0° C. was added 0.1 ml DMF followed by the addition of oxalyl chloride (3.35 ml) over 20 min. The solution was stirred for 2 h then concentrated. The crude acid chloride was dissolved in chloroform (150 ml) and cooled to 0° C., whereupon concentrated ammonia solution (6 ml) was added over 15 min and the resulting solution stirred for 2 h. The reaction mixture was washed with water and the organic phase dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed over silica using a gradient elution from ether to 2:1 acetone/ether to yield the title compound (2.86 g, 43%). 1H-NMR (CDCl3) δ 1.96 (2H, app q), 2.21 (2H, t), 2.65 (2H, t), 5.41 (2H, br s), 6.96 (2H, m), 7.14 (2H, m). MS (APCI+) M+1=182, C10H12FNO requires 181.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:14])([F:13])[CH2:10][CH:11]=[CH2:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:15]([O:17][CH:18]([SiH3:22])[O:19][CH2:20][CH3:21])[CH3:16]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]([F:14])([F:13])[CH2:10][CH2:11][CH2:12][SiH2:22][CH:18]([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C=CCC(F)(F)P(=O)(OCC)OCC
Reactant: CCOC([SiH3])OCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CCOC(OCC)[SiH2]CCCC(F)(F)P(=O)(OCC)OCC
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
5 g (23.4 mmol) diethyl-1,1-difluorobut-3-enylphosphonate was mixed with 7.5 g (56 mmol) diethoxymethylsilane and several drops of hydrogen hexachloroplatinate (IV) solution (5% in isopropanol). After stirring at 60° C. overnight, the solution was evaporated under reduced pressure to remove the reactants and product [4-(diethoxymethylsilyl)-1,1-difluoro-butyl]-phosphonic acid diethyl ester (DMSFP, 6 g, 16.6 mmol, yield 71%) was provided. See Scheme 7. 1H NMR (CDCl3): δ(ppm) 0.12(3H, s), 0.65 (2H, m), 1.21 (6H, t, JH-H=6.98), 1.35 (6H, 6, JH-H=7.06), 1.65 (2H,m), 2.15 (2H,m), 3.75 (4H, q, JH-H=6.98), 4.26 (4H, q, JH-H=7.06).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:16]([CH:17]=1)[C:15](=[O:18])[C:14]1[C:9](=[CH:10][CH:11]=[C:12]([C:19]([OH:21])=[O:20])[CH:13]=1)[N:8]=2)[CH3:3].Br.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31]Br)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][O:20][C:19]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]2[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:17][N:16]2[C:15]3=[O:18])=[O:21])[CH:24]=1
Reactant: BrCCCc1cccnc1
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cc3c(=O)n2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc2nc3ccc(C(=O)OCCCc4cccnc4)cc3c(=O)n2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A suspension of 0.60 g of 8-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid, 0.63 g of 3-(3-pyridyl)propyl bromide hydrobromide and 0.62 g of potassium carbonate in 50 ml of dimethylformamide was stirred at a bath temperature of 70° C. for three hours. The mixture was diluted with dichloromethane and washed successively with water, 10% sodium hydroxide, and water and was dried over K2CO3. The residue obtained after evaporation afforded 0.40 g of 8-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid 3-(3-pyridyl)propyl ester, mp 111°-112° C.
Reaction SMILES: [N:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:11]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C@H:12]([CH3:14])[NH:8][C:7]1[CH:9]=[CH:10][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Reactant: CC(=O)C(=O)OCC(C)C
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(N=[N+]=[N-])cc1

Procedure:
Following General Procedure AA above and using 4-azidoaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.3 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(Cl)c(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
Under argon, 3,4-dichlorophenyl 4-hydroxyphenyl ketone (154 mg) obtained in Example 121 and 4-dimethylaminopyridine (77 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 3 hours. 4-Chloro-6,7-dimethoxyquinoline (129 mg) was added, and the admixture was refluxed with heat for 21 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by thin layer chromatography on silica gel eluting with hexane/acetone (2/1) to obtain 81 mg of the title compound (yield: 31%).
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[CH:3]1[Br:23].N12CCCCC1C=NCCC2.O>CN(C)C=O>[Br:23][C:3]1[C:4]2[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=2[N:6]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]=1
Reactant: O=C(N1c2ccccc2C(Br)C(Br)c2ccccc21)C(F)(F)F
Agent: C1=NCCCN2CCCCC12
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N1c2ccccc2C=C(Br)c2ccccc21)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of 138.1 g of 10,11-dibromo-10,11-dihydro-5-(trifluoroacetyl)-5H-dibenz[b,f]azepine in 580 ml of dimethyl formamide is treated at 0°-10° C with 114.5 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene and stirred for 1 hour at the same temperature. The dark solution is then poured into a mixture of water and ice and the resultant suspension is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation, to yield crude, syrupy 10-bromo-5-(trifluoroacetyl)-5H-dibenz[b,f]azepine which is directly processed further.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=2.[NH2:17][CH2:18][CH2:19][OH:20]>C(O)(C)C.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:17][CH2:18][CH2:19][OH:20])=[CH:9][CH:8]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=2
Reactant: NCCO
Reactant: FC(F)(F)c1ccc2c(Cl)c(Br)cnc2c1
Solvent: CC(C)O
Solvent: O
Product: OCCNc1c(Br)cnc2cc(C(F)(F)F)ccc12

Procedure:
A solution of 12.4 g of 3-bromo-4-chloro-7-trifluoromethylquinoline and 6.1 g of 2-aminoethanol in 30 ml of isopropanol was heated at reflux for 4 hours. The mixture was cooled and diluted with 150 ml of water and the solid was collected and recrystallized from isopropanol. The yield was 8.2 g, mp 140°-141° C.