Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:5][N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:24]3[N:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]#[N:31])=[CH:13][CH:14]=2)=[CH:5][N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccn2)cc1COc1ccc(CO)cc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)cc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a mixture of [4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]phenyl]methanol (2.00 g), 2-chloro-3-cyanopyridine (1.00 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.30 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate and concentrated to give crystals (2.48 g, 92%) of 2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinonitrile. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 108-109° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][C:18]=1[F:28])=O)(C)(C)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[C:30]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:31]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][C:18]=1[F:28]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(COc2ccc(CCC(=O)O)cc2F)cc(Oc2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCOc1cc(COc2ccc(CCC(=O)O)cc2F)cc(Oc2ccccc2)c1
Reaction time: 15 h
Yield: 89 %

Procedure:
To 3-{4-[(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}-5-phenoxybenzyl)oxy]-3-fluorophenyl}propanoic acid (0.20 g, 0.38 mmol) was added a solution of hydrochloric acid in ethyl acetate (4 N, 1 mL), and the mixture was stirred 15 hours. The reaction solution was concentrated under reduced pressure, and the resulting white powders were separated by filtration, washed with ethyl acetate and dried to give the title compound. Yield 89%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][NH:19][C:20]([C:22]1[CH:27]=[C:26](OC2C=CC([N+]([O-])=O)=C([N+]([O-])=O)C=2)[CH:25]=[CH:24][N:23]=1)=[O:21]>CN(C=O)C>[CH3:18][NH:19][C:20]([C:22]1[CH:27]=[C:26]([O:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:16][CH:15]=2)[CH:25]=[CH:24][N:23]=1)=[O:21]
Reactant: CNC(=O)c1cc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)ccn1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred RT slurry of NaH (2.24 g of 60% oil dispersion, 55.9 mmol) in 40 mL DMF was added 4-benzyloxyphenol (11.2 g, 55.9 mmol). The mixture was stirred for 10 min before adding 4-chloro-pyridine-2-carboxylic acid methylamide (Example 2 Step A, 3.18 g, 18.6 mmol). The reaction was stirred at RT for 5 min, then at 75° C. for 2 h, and finally at 85° C. for 6 h. The reaction was cooled to RT, quenched with saturated aqueous NaHCO3, then diluted with Et2O and 6 N NaOH. The layers were separated, and the organic layer was washed twice with 6 N NaOH, once with brine, dried over Na2SO4, filtered, and concentrated in vacuo, to yield the title compound as a light salmon-colored solid. MS (MH+)=335.1; MW Calc'd 334.38 for C20H18N2O3.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=Cc3ccc(O)cc3OC2)cc1
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To a stirred solution of compound 1 (0.2 g, 0.58 mmol) in dry CH2Cl2 (4 mL), a solution of BCl3 (1 M, 0.7 mL, 0.7 mmol) in CH2Cl2 was added dropwise at 0° C. under nitrogen. After stirring for 10 min, the mixture was quenched with ice water and a saturated NaHCO3 solution (10 mL), and then stirred for a further 20 min. After extraction with CH2Cl2 (15 mL×6), the organic layers were combined, washed with brine, and dried with anhydrous MgSO4. After filtration, the filtrate was concentrated in vacuo, followed by purification via silica gel column chromatography (ethyl acetate/n-hexane=1:4), thus giving the title compound 2b as a colorless crystal (0.12 g, 81% yield).
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].OO.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CO>[C:1]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(C(C)=O)CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CC(=O)C1CCOCC1
Temperature: 35 °C
Yield: 88.2 %

Procedure:
In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 202 g (1.0 mol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 95% and synthesized in the same manner as in Reference example 1 and 720 ml of methanol, and the temperature of the mixture was raised to 35° C. with stirring. Then, to the mixture was gently added dropwise a mixed solution comprising 201 g (2.0 mol) of 35% by weight aqueous hydrogen peroxide solution and 91 ml (0.73 mol) of 8 mol/l aqueous sodium hydroxide solution, and the mixture was reacted at 40° C. for 5 hours with stirring. After completion of the reaction, to the resulting reaction mixture was added a saturated aqueous sodium sulfate solution to decompose the remaining hydrogen peroxide, then, the mixture was concentrated under reduced pressure, and the concentrate was extracted three times with 500 ml of ethyl acetate. The organic layer was distilled under reduced pressure (90 to 92° C., 2.0 kPa) to give 113 g (Isolation yield: 85%) of 4-acetyltetrahydropyran with a purity of 99% (areal percentage by gas chromatography) as a colorless liquid.
Reaction SMILES: [CH3:1][NH2:2].[NH:3]1[C:12](=O)[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]1=2>[Ti](Cl)(Cl)(Cl)Cl.O1CCCC1>[CH3:1][NH:2][C:12]1[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[N:3]=1
Reactant: CN
Reactant: O=C1CCc2ncc3ccccc3c2N1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CNC1=Nc2c(ncc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of anhydrous methylamine (30 ml), 1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one (5.46 g) and sieve dried tetrahydrofuran (450 ml) was stirred and chilled with ice water, and was treated dropwise over 30 minutes with a preformed complex of titanium tetrachloride (3.0 ml, 5.2 g) and sieve dried tetrahydrofuran (220 ml). The resultant mixture was stirred with cooling for 1 hour, followed by stirring for 3.5 hours at ambient temperature. After standing overnight at ambient temperature the reaction was quenched with water (100 ml) and 10% NaOH solution (30 ml). The suspension was filtered and concentrated to give a biphasic residue (pH 10). The mixture was extracted with dichloromethane (2×200 ml) dried (Na2SO4), filtered and evaporated to dryness (residue wt: 7.66 g). The residue was purified by HPLC (silica gel, eluted with 10% (v/v) methanol in ethyl acetate). The appropriate fractions were concentrated to give 5.1 g of pure product which was recrystallized from toluene (35 ml) to afford 3.56 g of crystals, m.p. 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:13]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:13][N:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[S:9]1(=[O:12])=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: O=S1(=O)NCc2cccc(Cl)c21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1Cc2cccc(Cl)c2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 16.6 g of 7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide in 85 mls of dry dimethylformamide was cooled and treated with 10 g of potassium t-butoxide at such a rate that the temperature remained below 6° C. The resulting suspension was stirred at 5° to 10° C. for 30 minutes, treated with 6.1 mls of methyl iodide at 10° to 15° C. and stirred at room temperature for 16 hours. The mixture was poured into ice water and the resulting solid was filtered, washed with water and dried in vacuo at 50° C. for 1.5 hours to give 15.4 g of the title compound as a pinkish solid, m.p. 95°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[CH:6][CH:7]=1
Reactant: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cc(F)cc12

Procedure:
2.0 mg (0.03 mmol) of copper powder were added to 2.21 g (3.08 mmol) of the compound from Example 19A with a purity of 64% in 23 ml of pyridine and 6 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 1.29 g (82% of theory) of the title compound with a purity of 79%.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH2:13][CH3:14])=[CH:11][C:10]2[C:5](=[N:6][C:7](=[O:16])[C:8](=[O:15])[N:9]=2)[CH:4]=1)[CH3:2].FC(F)(F)C(O)=O.[N+:24]([O-])([O-:26])=[O:25].[K+]>O>[N+:24]([C:11]1[C:12]([CH2:13][CH3:14])=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[C:10]=1[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:26])=[O:25]
Reactant: CCc1cc2c(cc1CC)=NC(=O)C(=O)N=2
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1CC
Yield: 69.1 %

Procedure:
6,7-Diethyl-2,3-quinoxalinedione 25 (218 mg, 1.0 mmol) was added to trifluoroacetic acid (8 mL; Sigma). To this suspension was added potassium nitrate (121.2 mg, 1.2 mmol; Baker) in one portion with stirring under N2. The reaction was stirred at room temperature for 48 h. Trifluoroacetic acid was evaporated in vacuo to give a residue. Water (10 mL) was added to this residue with vigorous stirring. A yellow solid precipitated, which was collected by suction filtration and dried in vacuo to give 182 mg (69%) of the title compound 26 as a yellow solid; mp 270-272° C. (dec.); 1H NMR (DMSO-d6,300 MHz) δ 1.137 (m, 6H), 2.622 (m, 4H), 7.088 (s, 1H), 11.762 (s, 1H), 12.028 (s, 1H). EIMS m/e 263 (100, M+). (HPLC purity 100%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1.S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO>[CH3:15][O:8][C:7]([C:3]1[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cccc(C)c1
Temperature: 5 °C
Yield: 93 %

Procedure:
To a solution of m-toluic acid (175 g, 1.28 mol) in methanol (2 L) was added dropwise thionylchloride (612 g, 5.14 mol) under stirring at 5° C. The mixture was refluxed overnight, then the solvent evaporated. The residue obtained was treated with a 10% aqueous NaHCO3 solution (pH ˜8). The product was extracted with ethyl acetate, washed with water and dried. The solvent was removed and the crude was purified by column chromatography (pet ether/ethyl acetate) to give methyl-m-toluate as colorless liquid (180 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:42][CH2:43][CH2:44][O:45]S(C)(=O)=O)=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:52]O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:42][CH2:43][CH2:44][O:45][CH3:52])=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)C1
Agent: [H-]
Agent: [Na+]
Product: COCCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described in example 14(a), the crude (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was treated with sodium hydride/methanol to yield the (3R,4R)-3-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 651 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[C:5]([C:12]([Cl:18])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c2[nH]c(=O)oc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c2[nH]c(=O)oc12

Procedure:
A stirred suspension of 4-fluoro-1,3-benzoxazol-2-one-7-carboxylic acid (1.79 g) in dry dichloromethane was treated with oxalyl chloride (0.97 g), followed by N,N-dimethylformamide (3 drops) to initiate the reaction. Stirring was maintained under reflux conditions for 1.5 hours and the mixture evaporated to dryness to give 4-fluoro-1,3-benzoxazol-2-one-7-carboxylic acid chloride, used in the next stage without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][CH3:18])=[CH:9][CH:8]=1)[CH3:2].Cl[CH:21]([C:23]1[C:24]([CH3:39])=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)[CH3:22].[Na+].[I-].C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]([CH3:18])[CH:21]([C:23]2[C:24]([CH3:39])=[N:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC)c2ccccc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)COc1ccc(N(C)C(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc12
Temperature: 40 °C
Reaction time: 20 h

Procedure:
0.095 g (0.37 mmol) of the above prepared (4-methylamino-naphthalen-1-yloxy)-acetic acid ethyl ester and 0.220 g of [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (see below 1G], 2.0 eq.) were treated in 2.8 ml of DMSO with 0.110 g (1 eq.) of NaI and 0.168 g (1.5 eq.) of DBU. After stirring for 20 h at 40° C., the reaction mixture was poured onto crashed ice/KHSO4, extracted twice with AcOEt, washed with water and brine, and dried over sodium sulfate. Evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15), afforded 0.055 g of the title compound as light brown oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:36]=[CH:35][C:11]([C:12]([C:14]2[CH:34]=[CH:33][C:17]([CH2:18][S:19][C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH3:32])[N:21]=3)=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1)(=O)C.[OH-].[Na+].ClCCl>CO>[CH3:30][N:29]1[C:28](=[O:31])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:32])[N:21]=[C:20]1[S:19][CH2:18][C:17]1[CH:33]=[CH:34][C:14]([C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:36][CH:35]=2)=[CH:15][CH:16]=1
Reactant: CC(=O)OCCOc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCO)cc4)cc3)n(C)c(=O)c12
Yield: 79.7 %

Procedure:
A solution of 2-[4-[4-(2-acetoxyethoxy)benzoyl]-benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (1.75 g) and 1N-aqueous sodium hydroxide solution (15 ml) in methanol (50 ml)-dichloromethane (25 ml) was stirred at room temperature for 3 hours. This reaction mixture was extracted with dichloromethane and the extract was dried and concentrated. The residue was recrystallized from ethyl acetate to provide the title compound as colorless solid (1.278 g).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)[CH2:17][C@@H:12]2[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[OH:9][C@@H:10]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)[CH2:17][C@@H:12]2[CH2:11]1
Reactant: O=C(O[C@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O[C@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 0.52 g (1.45 mmol) of (7S,8aS)-2-(5-chloropyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazin-7-yl benzoate (Example 17) in 50 mL of methanol was treated with 50 mL of 15% aqueous sodium hydroxide and stirred at ambient temperature for 30 minutes. The solent was concentrated by half in vacuo and the residue extracted with chloroform (3×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated Purification by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.25 g (68%) of the title compound. Mp (base) 167-168° C. m/z (MH+) 254.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[CH3:32]OC1C=C2C(=CC=1)NC(C)=C2CC(O)=O.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[Cl:27][C:4]1[CH:5]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][C:15]=2[CH3:32])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Product: COc1ccc2[nH]c(C)c(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid in step 10 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 10 (B), the title compound was prepared. MS (ESI) (M+H)+=476.05 1H-NMR (300 MHz, CD3OD) δ 7.42 (s, 2 H), 7.18 (d, J=8.42 Hz, 1 H), 6.96 (d, J=2.56 Hz, 1 H), 6.64-6.84 (m, J=2.56 Hz, 1 H), 4.48 (s, 2 H), 3.88 (s, 2 H), 3.80 (s, 3 H), 2.40 (s, 3 H), 2.19 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].CN(C=O)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:16][NH:17][C:18](=[O:28])[NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]([OH:27])=O)[N:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CCOC(C)=O.C(N(CC)CC)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:16][NH:17][C:18](=[O:28])[NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[O:27])[N:24]=1
Reactant: CNCCOC
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN(C)C(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1

Procedure:
2-methoxy-N-methylethanamine (56 μL, 0.625 mmol, 2.5 eq) was added to a DMF (2 mL) solution of 2-(3-(3,4-dichlorobenzyl)ureido)thiazole-4-carboxylic acid (87 mg, 0.25 mmol), TBTU (93 mg, 0.29 mmol, 1.15 eq) and triethylamine (100 μL). After an hour stirring, an aqueous work-up with EtOAc afforded the title compound. 1H NMR (400 MHz, CDCl3): 11.27 (s, 1H), 8.70 (s, 1H), 7.49 (d, 1H), 7.35 (dd, 1H), 7.20 (dd, 1H), 4.40 (d, 2H), 2.80-3.70 (m, 7H, rotamers). MS (ES+): M/Z 417 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[NH:14][CH:15]=[N:16][CH:17]=1)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:24])[C:7](=[O:12])[C:6]([C:13]1[NH:14][CH:15]=[N:16][CH:17]=1)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=c1[nH]c2ccc(Br)cc2c(-c2ccccc2)c1-c1cnc[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2cnc[nH]2)c(-c2ccccc2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A flask containing 6-bromo-3-(3H-imidazol-4-yl)-4-phenyl-1H-quinolin-2-one (23 mg, 0.063 mmol) (Example 134), K2CO3 (30 mg, 0.22 mmol), methyl iodide (4 μL, 0.063 mmol) and 0.1 mL of DMF was stirred at 25° C. for 3 hrs. The compound was purified by RP-HPLC, eluting with 30-70% CH3CN in 0.1% TFA/H2O over 20 mins to give 13 mg (42%) the title compound as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.82 (s, 1H), 7.90 (dd, 1H), 7.70 (d, 1H), 7.62 (m, 3H), 7.34 (m, 3H), 6.60 (s, 1H), 3.92 (s, 3H). Diff Noe, irradiation at 3.92 ppm (N—CH3) enhanced 7.70 ppm (d, 1H, H-8). Mass spectrum (ESI, m/z) calcd. for C19H1BrN3O2 379.0, found 380.0 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(CC1C(=O)C=C(C)CC1)(OCC)=O>C1COCC1>[C:24]([CH2:23][CH:10]1[C:9](=[O:13])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: O=C1C=C(c2ccccc2)CCC1
Agent: CC(C)[N-]C(C)C
Agent: CCOC(=O)CC1CCC(C)=CC1=O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCC(c2ccccc2)=CC1=O
Yield: 86.8 %

Procedure:
The reaction of 3-phenyl-2-cyclohexen-1-one (3.0 g, 17.4 mmoles) in 10 ml of THF with lithium diisopropylamide (19.2 mmoles) followed by ethyl bromoacetate (3.5 g, 20.9 mmoles) in 10 ml of THF, at -78° C. under argon, was conducted in a similar manner to the synthesis of 6-(carbethoxymethyl)-3-methyl-2-cyclohexen-1-one described in Example II. A yield of 3.90 g (87%) of 6-(carbethoxymethyl)-3-phenyl-2-cyclohexen-1-one was obtained.
Reaction SMILES: C([O:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:23])[C:11]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:24]2[CH2:26][CH2:25]2)[C:7]1=[O:27])(C)(C)C>C(O)(C(F)(F)F)=O>[CH:24]1([N:8]2[C:9]3[C:14](=[CH:13][C:12]([F:17])=[C:11]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[C:10]=3[F:23])[C:15](=[O:16])[N:6]([OH:5])[C:7]2=[O:27])[CH2:26][CH2:25]1
Reactant: CC(C)(C)On1c(=O)c2cc(F)c(N3CCCC3)c(F)c2n(C2CC2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cc(F)c(N3CCCC3)c(F)c2n(C2CC2)c(=O)n1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 3-tert-butoxy-1-cyclopropyl-6,8-difluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example U-3, 0.52 g) in TFA (10 mL) was allowed to stir overnight at ambient temperature. The mixture was then concentrated and the product triturated with diethyl ether (repeated three times). The solid was filtered and washed with diethyl ether and dried to provide 0.35 g of the title compound as a solid, mp 228-230° C.