Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.[I:14]C(I)I.N(OC(C)(C)C)=O>C1COCC1>[I:14][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: IC(I)I
Reactant: Nc1ccc2c(c1)CCCNC2=O
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: O=C1NCCCc2cc(I)ccc21
Temperature: 50 °C
Yield: 67.5 %

Procedure:
7-Amino-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (may be prepared as described in: Preparation of benzazepinylpyrrolidonylsulfonamides as Factor Xa inhibitors; WO2007059952) (500 mg, 2.84 mmol) and triiodomethane (2234 mg, 5.67 mmol) were dissolved in THF (100 ml). Then 1,1-dimethylethyl nitrite (0.675 ml, 5.67 mmol) dissolved in THF (20 ml) was added drop-wise over 20 minutes and the resultant solution stirred for 1 hour. The mixture was heated at 50° C. for 30 minutes. Most of the solvent was removed by evaporation and the crude subjected to biotage chromatography (EtOAc/hexane 3:1) to yield the title compound (550 mg) as a pale yellow solid. MS (ES) C10H10INO requires 287: found 287.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:1]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]2=[O:16])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 25 °C

Procedure:
41.1 g (0.3 mol) of p-aminobenzoic acid and 300 M of acetic acid were put into a 250 M flask to dissolve the p-aminobenzoic acid in the acetic acid, and then 29.4 g (0.3 mol) of maleic anhydride was slowly added thereto at 10° C. to obtain a yellow precipitate. This precipitate was recrystallized with a solution of DMF (dimethylformamide) and ethanol (50:50, w/w) to form an intermediate. The intermediate was treated at 85° C. for 15 minutes using sodium acetate and acetic anhydride, was cooled to room temperature, and was then precipitated in an ice water bath to obtain a precipitate. The obtained precipitate was recrystallized with a solution of ethyl acetate and n-hexane (50:50, w/w) to obtain N-(p-carboxyphenyl)maleimide.
Reaction SMILES: CC[O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=O.[H-].[Na+].[CH3:18][C:19]1[CH2:24][CH2:23][CH2:22][C:21]([CH3:26])([CH3:25])[C:20]=1[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O.C(=O)(O)[O-].[Na+].[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH3:7]/[C:6](=[CH:31]\[CH2:30][CH2:29][CH2:28][CH2:27][C:20]1[C:21]([CH3:25])([CH3:26])[CH2:22][CH2:23][CH2:24][C:19]=1[CH3:18])/[CH2:4][OH:3]
Reactant: CC1=C(CCCCC=O)C(C)(C)CCC1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=C(CCCC/C=C(\C)CO)C(C)(C)CCC1
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a stirred solution of triethyl 2-phosphonopropionate (4.2 g) in THF (25 ml) under nitrogen is added sodium hydride (0.69 g of 60% dispersion in oil). After 30 minutes, 5-(2,6,6-trimethyl-1-cyclohexen-1-yl)pentanal (3.09 g) is added, and the mixture is stirred at reflux for16 hr. The reaction is cooled, poured into aqueous sodium bicarbonate, and extracted with ether. The extracts are concentrated and chromatographed with 30% dichloromethane in hexane to provide (2E)-2-methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-heptenoic add ethyl ester as a colorless oil (2.4 g). This material (2.09 g) is reacted with diisobutylaluminum hydride (10 ml of 1.5M toluene solution) in toluene (20 ml) at -20° , stirred at 0° for 3 hr, then stirred for 16 hr with 1.0N sodium hydroxide solution. The mixture is extracted with ether, and the organic phase is concentrated and chromatographed with dichloromethane to provide 1.6 g of (2E)-2-methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-heptenol as a colorless oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN.[Li].O>O1CCCC1.C(O)(C)(C)C>[CH2:1]1[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)CCNC2
Agent: CN
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: C1=CCC2CCNCC2=C1
Temperature: -10 °C

Procedure:
Typically, the tetrahydroisoquinoline was suspended or dissolved in a cosolvent such as tetrahydrofuran or t-butyl alcohol. This mixture was cooled to −10° C. and methylamine was added and the temperature was maintained at −10° C. The lithium metal was charged in portions and the reaction mixture was stirred at −10° C. for another 30 minutes to about 2 hours after sufficient lithium metal was charged. The reaction mixture was warmed to room temperature and then added to water to produce the product hexahydroisoquinoline as a precipitate.
Reaction SMILES: [K].[C:2]1([CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:19](Cl)[N:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:13][S:10]([CH2:9][CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:11])=[O:12])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: NS(=O)(=O)CCc1ccccc1
Agent: [K]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)CCc2ccccc2)cc1
Temperature: 5 °C
Yield: 59.6 %

Procedure:
A solution of 2-phenyl-ethanesulfonic acid amide potassium salt (3.0 g), 4,6-dichloro-5-p-tolyl-pyrimidine (2.15 g) and Hunig's base (1.57 ml) in DMSO (50 ml) was stirred at rt for 20 h before it was diluted with water (500 ml) and extracted twice with diethyl ether (250 ml). The aqueous phase was acidified with acetic acid. The resulting suspension was cooled to 5° C. and filtered. The solid material was washed with water and diethyl ether, and dried at 40° C. under high vacuum to give 2-phenyl-ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (2.08 g) as a grey powder. LC-MS: tR=5.23 min, [M+1]+=388.18, [M−1]−=386.14.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:14]2[C:9](=[C:10]([Cl:16])[CH:11]=[CH:12][C:13]=2[Cl:15])[C:7](=[O:8])[O:6]1)#[N:4].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1>>[C:3]([C:5]1([C:21]2[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=2)[C:14]2[C:9](=[C:10]([Cl:16])[CH:11]=[CH:12][C:13]=2[Cl:15])[C:7](=[O:8])[O:6]1)#[N:4]
Reactant: N#CC1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)ccc(Cl)c32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
21.5 g of NaH in oil dispersion are added to 112.75 g of 3-cyano-4,7-dichlorophthalide and 96.7 g of 4,6-dimethoxy-2-methylsulfonyl-pyrimidine. (The hydride is washed with hexane, the hexane removed by suction and the residue covered with DMF and cooled in an ice bath.) The reaction mixture is left to stir overnight at RT and the solution then poured into 3 L of water containing 15 ml of conc. H2SO4 and stirred mechanically until a viscous gum formed around the stirred blade. The water layer is decanted and extracted with 3×400 ml of toluene, the first two extracts added to the gum and the mixture stirred until the gum dissolved. The toluene solution is washed 2×100 ml of water and 1×100 ml of toluene and the combined toluene layers dried over Na2SO4 concentrated to 400 ml and left to stand overnight. The still homogeneous solution is flash-chromatographed over silica gel with toluene (250 ml fraction 5) fractions 5-9 are combined and stripped to give 30 g of the title product m.p. 123°-126° C.
Reaction SMILES: C[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[Cl:14]C1C=CC=C(N)C=1C(OC)=O.N([O-])=O.[Na+].S(=O)=O.ClS(C1C=CC=C(Cl)C=1C(OC)=O)(=O)=O.[OH-].[NH4+]>C(O)(=O)C.Cl.O>[Cl:14][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7]
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Reactant: COC(=O)c1c(N)cccc1Cl
Agent: COC(=O)c1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NS(=O)(=O)c2cccc(Cl)c21
Yield: 62 %

Procedure:
4-Chlorosaccharin was prepared by the same method as used for the preparation of 4-methylsaccharin using 4.22 g (0.023 mol) of methyl 6-chloroanthranilate in 22 ml of acetic acid and 40 ml of concentrated hydrochloric acid and 1.68 g (0.024 mol) of sodium nitrite in 7 ml of water to prepare the diazonium salt which was added to 1.93 g (0.011 mol) of cupric chloride dihydrate and 6.5 g of sulfur dioxide in 30 ml of acetic acid and 5 ml of water. The resulting methyl 2-chlorosulfonyl-6-chlorobenzoate was treated with 150 ml of ammonium hydroxide as described above to afford 3.07 g (62%) of 4-chlorosaccharin as a pale yellow solid, mp 245°-246° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:5]=[C:4]2[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:18](=[O:21])[NH:19][CH2:20][C:3]=12.[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][C:31]=2[CH3:30])[C:35]([OH:37])=[O:36])[C:3]2[CH2:20][NH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: CCN(CC)CCCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 150 °C
Yield: 25.8 %

Procedure:
To 5-chloro-7-{[3-(diethylamino)propyl]amino}-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (207 mg, 0.488 mmol) in 1,4-dioxane (7.5 mL) and water (2.5 mL) was added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.192 g, 0.733 mmol), tetrakis(triphenylphosphine)-palladium(0) (28.3 mg, 0.024 mmol), and potassium carbonate (270 mg, 1.95 mmol). The mixture was heated with microwave for 15 min at 150° C., and then allowed to cool to room temperature. The mixture was concentrated and separated by HPLC to afford the title compound (66 mg, 26%). LC-MS m/z 525 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(O)c1)C(=O)O
Reaction time: 2 h
Yield: 102.1 %

Procedure:
Methyl 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (0.91 g, 3.1 mmol) was taken up in methanol (30 mL) at rt and the lithium hydroxide monohydrate (0.51 g, 12.3 mmol) in water (10 mL) was added. The reaction was complete after stirring for 2 h. The methanol was removed under reduced pressure to give an aqueous layer which was partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoic acid (0.89 g, 100%). Analytical LCMS (M+H-Boc)+: m/z=181.9.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1)[CH2:6][CH2:7]2>C1COCC1.[Pd]>[F:12][C:11]1[C:2]([F:1])=[C:3]2[C:8]([CH2:7][CH2:6][CH:5]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH2:4]2)=[CH:9][CH:10]=1
Reactant: CCCC1CCC(C2=Cc3c(ccc(F)c3F)CC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCc3ccc(F)c(F)c3C2)CC1

Procedure:
76.0 g (0.26 mol) of 5,6-difluoro-3-(4-propylcyclohexyl)-1,2-dihydronaphthalene are hydrogenated at RT and atmospheric pressure for 19 h in 500 ml of THF in the presence of Pd/C (5% of Pd). The reaction solution is filtered and evaporated to dryness. The residue is used for the following reaction without further purification.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:20]1([C:2]2[N:6]([S:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=2)[CH2:22][CH2:21]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2CC2)n(S(=O)(=O)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 21.7 %

Procedure:
Under an argon atmosphere, a suspension of methyl 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (2.11 g), cyclopropylboronic acid (683 mg), palladium(II) acetate (69 mg), tricyclohexylphosphine (174 mg) and tripotassium phosphate (4.55 g) in toluene (27 mL)-water (1.3 mL) was stirred at 100° C. for 4 hr. After cooling, the reaction mixture was diluted with water (50 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→8:2) to give the title compound as a yellow oil (yield 406 mg, 22%).
Reaction SMILES: C(O)C.Cl[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:12]=1.[S-:24][C:25]#[N:26].[K+].[I-].[K+]>C(OCC)(=O)C.CCCCCC>[S:24]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:12]=1)[C:25]#[N:26]
Reactant: N#C[S-]
Reactant: Cc1ccc(OCCCCCCl)cc1SCC(F)(F)F
Agent: [I-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(OCCCCCSC#N)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 84.4 %

Procedure:
To 100 ml of ethanol were added 2.0 g (6.1 mmol) of 5-chloropentyl-{4-methyl-3-(2,2,2-trifluoroethylthio)phenyl}ether, 4.0 g (41 mmol) of potassium thiocyanate and 0.10 g (0.61 mmol) of potassium iodide. The mixture was refluxed for 10 hours under heating and then allowed to cool to room temperature. The solvent was distilled off under reduced pressure. To the residue was added ethyl acetate to conduct extraction. The organic phase obtained was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 1.8 g (yield: 84%) of an intended product.
Reaction SMILES: [I-].[Na+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ccccc1
Agent: [I-]
Agent: [Na+]
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 20 h
Yield: 23 %

Procedure:
The procedure described in Example 13 was used except that the sodium iodide was omitted from the catalyst mixture, and the reaction time was 20 hours. Gas chromatograph analysis revealed that all of the chlorobenzene had been consumed to produce 77% benzene and 23% biphenyl.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c21
Reactant: C1CNCCN1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(N3CCNCC3)c(F)c21
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 0.45 g (1.58 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.54 g (6.27 mmol) of anhydrous piperazine, and 20 ml of acetonitrile was refluxed for three hours, then cooled to room temperature. The solids were filtered and washed with water, acetonitrile, and ether to give 0.48 g of the title compound, mp 223°-225° C.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C@@H:14]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15](OCC)=[O:16].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:13][C@@H:14]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOC(=O)[C@@H](C)CCCc1ccccc1
Reactant: COP(C)(=O)OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a stirring solution consisting of dimethyl methylphosphonate (23.37 g, 188.4 mmol) in THF (400 mL) at −78° C. was slowly added n-butyllithium solution (112 mL, 179 mmol, 1.6 M solution in hexane). The reaction mixture was stirred for 30 minutes, after which time, (S)-(+)-ethyl 2-methyl-5-phenylpentanoate (14mb(i), 28.1 g, 94.2 mmol) in THF (100 mL) was slowly added. The resulting reaction mixture was stirred at −78° C. for two hours and was then allowed to rise to room temperature overnight. The reaction mixture was treated with 5% KHSO4 and extracted with ethyl acetate three times. The organic layer was washed twice with 50:50 water-brine and the organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (60:40 v/v) afforded the title compound (11.9 g, 42%) as a clear oil, pure of unrelated components; TLC Rf 0.22 (solvent system: 60:40 v/v ethyl acetate-heptane); HPLC retention time 14.5 minutes, 5μ Chiralpak IA 250×4.6 mm, ultraviolet detector at 210 nm, 1 mL/min, chiral purity 97.8% (S), 2.19% (R); MS (ESI−) m/z 297.1 (M−H)−; 1H NMR (CDCl3) δ 7.28-7.21 (m, 2H), 7.17-7.12 (m, 3H), 3.76-3.71 (m, 6H), 3.10 (d, J=2.20 Hz, 1H), 3.04 (d, J=2.20 Hz, 1H), 2.79-2.70 (m, 1H), 2.54-2.62 (m, 2H), 1.74-1.54 (m, 3H), 1.42-1.24 (m, 1H), 1.07 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=+0.084/(0.0169 g/1.5 mL)(0.5)=+14.91° (c=1.13, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:15][CH2:14]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc(C3CCNCC3)[nH]n2)cc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cc(C3CCN(CCc4ccccc4)CC3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[3-(4-chlorophenyl)-1H-pyrazol-5-yl]piperidine (INTERMEDIATE 7, 4 g, 15.28 mmol) in 60 mL DMF was added K2CO3 (63 g, 45.8 mmol), and 2-(bromoethyl)benzene (2.3 mL, 16.8 mmol). The reaction mixture was stirred at ambient temperature overnight, diluted with EtOAc, and washed three times with water. The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. LC-MS m/z=366.17 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[C:12]2[CH2:11][N:10]([CH3:13])[CH2:9][CH:8]3[C:14]4[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=4[CH2:16][CH2:17][C:6]([C:7]=23)=[CH:5][C:4]=1[O:22][CH3:23]>I>[CH3:23][O:22][C:4]1[C:3]([OH:2])=[C:12]2[C:7]3[CH:8]([C:14]4[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=4[CH2:16][CH2:17][C:6]=3[CH:5]=1)[CH2:9][N:10]([CH3:13])[CH2:11]2
Reactant: COc1cc2c3c(c1OC)CN(C)CC3c1ccccc1CC2
Agent: I
Product: COc1cc2c3c(c1O)CN(C)CC3c1ccccc1CC2
Temperature: 0 °C

Procedure:
A suspension of the di(lower)alkoxy compound, 4,5-dimethoxy-2-methyl-1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline (1.0 g, 3.2 mmol, described in example 4) in 58% (v/w) hydriodic acid (30 mL) was stirred in a closed vessel for 3 weeks at 20°-22° C. The reaction mixture was poured into ice water (50 mL). The resulting precipitate was collected, washed with a small amount of water, and then partitioned between concentrated ammonium hydroxide-water (1:1, v/v) and ethyl acetate. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated to dryness to give the title compound as a yellow solid. The product was purified by converting it to its hydrochloride and then regenerating the free base (0.864 g) from the hydrochloride. When purified in this manner and recrystallized from chloroform-hexane, the title compound had mp 173°-174° C.; NMR (CDCl3) δ2.50 (s, 3H), 3.75 (s, 3H), 4.55 (m, 1H), 5.50 (broad, 1H), 6.34 (s, 1H), 7.10 (m, 3H), 7.50 (m, 1H); Anal Calcd for C19H21NO2 : C, 77.26% H, 7.17% N, 4.74%; Found: C, 77.36% H, 7.23% N, 4.68%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[N:14]([CH2:29][O:28][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)ccc2c1=O
Reaction time: 1 h
Yield: 92 %

Procedure:
Sodium metal (4.4 g, 19 mmol) was added to benzyl alcohol (100 ml) at ambient temperature and the mixture stirred for 30 minutes then heated at 80° C. for 1 hour. The mixture was then cooled to 40° C. and 7-fluoro-3,4-dihydroquinazolin-4-one (7.8 g, 47 mmol) was added. The reaction mixture was stirred at 130° C. for 4 hours and allowed to cool to ambient temperature and stirred for 18 hours. The solution was quenched with water (800 ml) and acidified to pH3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and ether and dried for 4 hours at 60° C. under high vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (7.02 g, 63%). 7-Benzyloxy-3,4-dihydroquinazolin-4-one (7.0 g, 27 mmol) was suspended in dry DMF (50 ml) and sodium hydride was added (1.22 g of a 60% suspension in mineral oil, 30 mmol). The reaction mixture was allowed to return to ambient temperarture, chloromethyl pivalate (4.75 g, 31.5 mmol) was added over 10 minutes and the mixture was stirred for 1 hour. The reaction mixture was quenched into water (250 ml), the aqueous phase adjusted to pH5 with 2M hydrochloric acid and extracted with ether (3×300 ml). The combined ether phases were washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The solid residue was triturated with isohexane, collected by filtration and dried under vacuum to give 7-benzyloxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (9.1 g, 90%). 7-Benzyloxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (8.0 g, 22 mmol) was dissolved in TFA (40 ml) and the mixture was heated at reflux for 3 hours then allowed to cool to ambient temperature and stirred for 18 hours. The TFA was removed by evaporation and the residue resuspended in a mixture of ether and aqueous sodium hydrogen carbonate solution. The solid was collected by filtration, washed with water and ether and dried at 40° C. for 3 hours under high vacuum to give 7-hydroxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (5.42 g, 90%).