Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.COC([C:14]1[C:15]2[CH:16]3[N:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]([CH2:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)[CH2:18][CH2:17]3)=O>C(Cl)Cl>[CH3:29][O:28][C:26]([C:24]1[CH:23]=[C:22]([N+:1]([O-:4])=[O:2])[C:21]2[CH2:20][CH:19]3[N:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]([CH2:17][CH2:18]3)[C:15]=2[CH:14]=1)=[O:27]
Reactant: CCOC(=O)N1C2CCC1c1c(cccc1C(=O)OC)C2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1c1cc(C(=O)OC)cc([N+](=O)[O-])c1C2
Reaction time: 0.5 h
Yield: 23 %

Procedure:
Concentrated nitric acid (5 mL) was added dropwise to a mixture of concentrated sulfuric acid (5 mL), 12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-3,12-dicarboxylic acid 12-ethyl ester 3-methyl ester (300 mg, 1.04 mmol) and CH2Cl2 (5 mL) at 0° C. The resulting brown solution was stirred at this temperature for 30 min before pouring onto ice-water and extracting with CH2Cl2 (2×5 mL). Drying over MgSO4, filtering and concentration gave a brown residue that was purified with silica gel chromatography (0-20% EtOAc in hexanes) to give 6-Nitro-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-4,12-dicarboxylic acid 12-ethyl ester 4-methyl ester as a clear oil (81 mg, 23%) 1HNMR (400 MHz, CDCl3) δ 8.5 (s, 1H), 8.0 (s, 1H), 5.2 (m, 1H), 4.7 (m, 1H), 4.1 (q, 2H, J=7.1 Hz), 4.0 (s, 3H), 3.6-3.5 (m, 1H), 3.0 (d, 1H, J=18.7), 2.3-2.2 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.3-1.2 (m, 3H); MS (m/e) 335 (M+1); and 5-Nitro-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-4,12-dicarboxylic acid 12-ethyl ester 4-methyl ester as a pale yellow solid (79 mg, 23%) as the 5-nitro compound. 1HNMR (400 MHz, CDCl3) δ 7.6 (s, 1H), 7.4 (s, 1H), 5.1 (m, 1H), 4.6 (m, 1H), 4.1 (q, 2H, J=7.3 Hz), 3.9 (s, 3H), 3.5-3.4 (m, 1H), 2.7 (d, 1H, J=17.4), 2.3-2.2 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.3-1.2 (m, 3H); MS (m/e) 335 (M+1); The regioisomers were distinguished by NOE and 1H-1H COSY
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].[C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[CH3:7].CI>CN(C)C=O.O>[C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:1])=[O:13])(=[O:8])[CH3:7]
Reactant: O=C([O-])O
Reactant: CC(=O)CCCC(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)CCCC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a rapidly stirred slurry of sodium bicarbonate (25 g) in a solution of 4-acetylbutyric acid (13 g, 0.1 mol) in dimethylformamide (150 ml) was added methyl iodide (47 g). After stirring overnight at room temperature under nitrogen, the reaction mixture was diluted with water (300 ml) and extracted with ethyl ether (250 ml). The organic phase was washed with water and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give 12 g of the title compound as a light yellow oil. The product can be purified by distillation: b.p. 59°-60° (0.1 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].I[CH3:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:21])[CH:17]=1)=[O:11]
Reactant: CI
Reactant: CC(C(=O)c1ccc(=O)[nH]c1)c1ccc(Cl)cc1Cl
Product: CC(C(=O)c1ccc(=O)n(C)c1)c1ccc(Cl)cc1Cl

Procedure:
In analogy to Example 195, 5-[2-(2,4-dichloro-phenyl)-propionyl]-1H-pyridin-2-one was alkylated with iodomethane to give the title compound as a colorless oil. MS (m/e)=310.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:5].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4](=[O:5])[C:6](=[CH:20][N:21]([CH3:23])[CH3:22])[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)OC(C)(C)C)C(=O)c1ccccc1Cl
Reaction time: 144 h
Yield: 57.6 %

Procedure:
1,1-Dimethylethyl 2-chlorobenzoylacetate (87 mg, 0.342 mmol) and N,N-dimethylformamide dimethyl acetal (50 μL, 45 mg, 0.375 mmol) were stirred in 1 mL of toluene. After 6 d, the reaction was concentrated in vacuo and the residue was subjected to flash chromatography. Elution with 1:1 hexanes/EtOAc afforded 61 mg (58%) of the title compound as an oil that solidified on standing, mp 97-99° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]CC2C=CC(OC)=C(OC)C=2)[N:5]2[N:20]=[C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:4]2[CH:3]=1.FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:6]1[N:5]2[N:20]=[C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COc1ccc(CNc2nc(Cl)cc3nc(-c4ccco4)nn23)cc1OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nc(Cl)cc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Into 260 mL of trifluoroacetic acid, 50.0 g (130 mmol) of Compound D was dissolved, and 50 g (333 mmol) of trifluoromethanesulfonic acid and 42 mL (390 mmol) of anisole were added thereto, followed by stirring at room temperature for about 2 hours. After completion of the reaction, trifluoroacetic acid was evaporated under reduced pressure, and the residue was poured into ice-water. The mixture was adjusted to be alkaline with a 2 mol/L aqueous sodium hydroxide solution. The precipitated solid was washed with hexane and was reslurried with chloroform to obtain 25.6 g of Compound E as a white solid (yield: 83%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].O1C=CCC1=O>>[C:3]([CH:2]1[CH2:9][CH2:8][O:7][C:1]1=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Agent: O=C1CC=CO1
Product: CC(=O)C1CCOC1=O

Procedure:
The mixture was distilled using a Raschig ring packed column and a Perkins Triangle Head. Seven fractions were obtained and analyzed by gas chromatography. Fractions 1-3 were found to be principally ethyl acetoacetate. Fraction 4 analyzed 11% ethyl acetoacetate and 42% of the desired lactone. Fractions 5 and 6 showed 98.4% lactone and 95.4% lactone, respectively. The yield of the desired lactone product ##STR10## (fractions 5 and 6) was 32%.
Reaction SMILES: Cl.[CH2:2]([N:4]=[C:5]=NCCCN(C)C)C.Cl.CNC.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[C:40]3[C:35](=[N:36][C:37]([CH3:41])=[CH:38][CH:39]=3)[N:34]([CH2:42][CH3:43])[C:33](=[O:44])[C:32]=2[CH2:45][CH2:46][C:47]([OH:49])=O)[CH:28]=[CH:29][CH:30]=1>O.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[C:40]3[C:35](=[N:36][C:37]([CH3:41])=[CH:38][CH:39]=3)[N:34]([CH2:42][CH3:43])[C:33](=[O:44])[C:32]=2[CH2:45][CH2:46][C:47]([N:4]([CH3:5])[CH3:2])=[O:49])[CH:28]=[CH:29][CH:30]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1c(=O)c(CCC(=O)N(C)C)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
Under ice cooling, 630 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 154 mg of dimethylamine hydrochloride and 0.53 ml of triethylamine were added successively to a 10 ml DMF solution containing 700 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. The residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) and then recrystallized from diisopropyl ether to obtain 262 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]-N,N-dimethylpropanamide as colorless crystals.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18](OS(C(F)(F)F)(=O)=O)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:51]([O:53][C:54]([C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1)=[O:55])[CH3:52].CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.C(O)C.O.CCOC(C)=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>[CH2:51]([O:53][C:54](=[O:55])[C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:18]2[C:17]3[CH2:33][N:34]([CH2:37][C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)[C:35](=[O:36])[C:16]=3[C:15]([O:14][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:24]3[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]3)[CH:57]=1)[CH3:52]
Reactant: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cccc(-c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)c1
Temperature: 120 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (43 mg, 0.07 mmol) dissolved in toluene (3 mL)/ethanol (0.6 mL)/water (0.4 mL) was added K2CO3 (29 mg, 0.21 mmol), (3-ethoxycarbonylphenyl)boronic acid (28 mg, 0.14 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (16 mg, 0.014 mmol). The reaction mixture in the flask was flashed with argon three times. It was then heated to 120° C. under argon 3 hours. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf 46=0.6, Rf 277=0.3) and LC/MS. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford crude 3-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-benzoic acid ethyl ester 277.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:13]2)[CH2:9]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[F:22][C:19]1[CH:18]=[CH:17][C:16]([N:12]2[CH2:11][CH:10]3[CH:14]([CH2:15][NH:8][CH2:9]3)[CH2:13]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(N2CC3CN(Cc4ccccc4)CC3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(N2CC3CNCC3C2)cc1
Yield: 69.3 %

Procedure:
To an ethanol solution (3.0 mL) of 2-benzyl-5-(4-fluorophenyl)octahydropyrrolo[3,4-c]pyrrole (52.0 mg, 0.175 mmol) synthesized in Reference Synthesis Example 225, palladium hydroxide-activated carbon catalyst (catalytic amount) was added and the resultant mixture was stirred under hydrogen atmosphere at room temperature for 2 days. After completion of the reaction, the reaction solution was filtered with Celite and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (25.0 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.B([C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([C:32]4[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=4)[C:37]([OH:39])=[O:38])=[CH:26][C:11]=3[C:12]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(B(O)O)cc1C(=O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(OC)c(C(=O)O)c3)cc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a 150 mL sealed tube was added 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.252 g, 3 mmol), 5-borono-2-methoxybenzoic acid (0.882 g, 4.50 mmol), cesium carbonate (1.466 g, 4.50 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.069 g, 0.060 mmol), dioxane (18 mL) and water (3.60 mL). The vial was sealed and heated in an oil bath over night at 85° C. The reaction mixture was then filtered through celite and concentrated in vacuo. Cold 0.5N HCl was then added and the heterogeneous mixture was stirred for 30 minutes. The resulting product, a white solid was filtered, washed with water and dried overnight to give a quantitative yield of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy benzoic acid which was carried on without further purification. LCMS m/z 420.92 (M+H), Rt 2.003 min., 87% purity.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[B:22](OC)([O:25]C)[O:23]C>CCOCC>[S:9]1[C:10]2[C:2]([B:22]([OH:25])[OH:23])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:7]=[CH:8]1
Reactant: COB(OC)OC
Reactant: Brc1cccc2ccsc12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cccc2ccsc12
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
A solution of 7-bromo-1-benzothiophene (19.9 g, 0.094 mol) in absolute ether (200 ml) was treated with a 1.6 M solution of n-butyllithium in hexane (0.14 mol, 88 ml) at −78° C. The solution was stiffed at −78° C. for 10 minutes then treated with trimethyl borate (15 ml, 0.14 mol). The mixture was allowed to warm to −10° C. then quenched with an excess of dilute hydrochloric acid. The organic layer was separated, dried, evaporated, and the residue was recrystallised from aqueous ethanol to yield the title compound (10 g, 60%).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][C:11]=1[Cl:23])([O:3]CC)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26]>>[NH2:26][CH2:25][CH2:24][NH:27][C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][C:11]=1[Cl:23])=[O:3]
Reactant: CCOC(=O)CCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: NCCN
Product: NCCNC(=O)CCCOc1ccc(C2=NNC(=O)CC2)cc1Cl

Procedure:
A solution of 4.5 g (13.3 mol) of 6-[4-carboethoxypropyloxy-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Example 23) in 12.0 g 199 mmol) of ethylenediamine is heated at 95° C. under N2 for 12 hrs. Volatiles are removed under vacuum and the residue recrystallized from EtOAc-methanol to give 3.65 g of 6-{4-[2-aminoethylcarbamoylpropyloxy]-3-chlorophenyl}-4,5-dihydro-3(2H)-pyridazinone as a white powder. Yield, 78%.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:20]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:22]=1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(Br)ccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2F)C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97.7 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (4.56 g, 32.10 mmol) in anhydrous 1,2-dimethoxyethane (25 ml) is added sodium methoxide (1.91 g, 35.10 mol) in one portion. After stirring at room temperature for 10 minutes a second solution of 5-bromo-2-fluorobenzaldehyde (5.93 g, 29.10 mmol) in anhydrous 1,2-dimethoxyethane (45 ml) is added dropwise, followed by stirring at 0° C. for a further 45 minutes. The reaction mixture is quenched with 2M hydrochloric acid (50 ml), then diluted with diethyl ether and the two phases separated. The aqueous phase is further extracted with diethyl ether (×2), then all organics are combined, washed with brine and dried over magnesium sulfate. After filtration the filtrate is concentrated in vacuo to afford 4-[1-(5-bromo-2-fluorophenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (9.30 g, 96%) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23].C(N(C(C)C)CC)(C)C.Cl>O.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11]([C:14]([NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[O:16])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: O=C(O)c1ncc(-c2cccc(F)c2)cc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CNC(=O)c1ncc(-c2cccc(F)c2)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a nitrogen inlet tube is charged 5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxylic acid, 10, (0.932 gm, 4 mmol), N,N′-carbonyldiimidazole (CDI) (0.97 g, 6 mmol) and dimethyl sulfoxide (5 mL). The reaction mixture is stirred at 45° C. for about 1 hour then cooled to room temperature. Glycine methyl ester hydrochloride (1.15 g, 12 mmol) is added followed by the dropwise addition of diisopropylethylamine (3.2 mL, 19 mmol). The mixture is then stirred for 2.5 hours at room temperature after which water (70 mL) is added. The contents of the reaction flask is cooled to 0° C. to 5° C. and 1N HCl is added until the solution pH is approximately 2. The solution is extracted with dichloromethane (100 mL) and the organic layer dried over MgSO4 for 16 hours. Silica gel (3 g) is added and the solution slurried for 2 hours after which the solids are removed by filtration. The filtrate is concentrated to dryness under reduced pressure and the resulting residue is slurried in methanol (10 mL) for two hours. The resulting solid is collected by filtration and washed with cold methanol (20 mL) then hexane and the resulting cake is dried to afford the desired product.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:32][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[O:23][CH:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)[C:9]=2[C:8]=1[CH3:33])=[O:6]>C1COCC1.CO>[F:31][C:27]1([F:30])[CH2:28][CH2:29][CH:24]([O:23][C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[NH:15][C:14]2[C:9]3[C:8]([CH3:33])=[C:7]([C:5]([OH:6])=[O:4])[S:32][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:25][CH2:26]1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.620 ml sodium hydroxide solution (2M) was added to 0.110 g 4-[2-(4,4-difluoro-cyclohexyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (cpd. 33.1) in 4 ml THF/MeOH (1/1). An additional aliquot of sodium hydroxide solution was added when the reaction mixture was stirred at rt overnight. After further 6 hours at rt the mixture was concentrated, the resulting aq. layer was adjusted to pH 4-5 with aq. 2 M aq.HCl and stirred under cooling for 30 minutes. Then the mixture was filtered, the filtercake was washed with water and dried.
Reaction SMILES: [N+](=C1C=CC2C(=CC=CC=2S([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]=[N+:24]=[N-:25])=[CH:19][CH:18]=2)(=O)=O)C1=O)=[N-].[N+:27](=[C:29]1[CH:38]=[C:37]([S:39](Cl)(=[O:41])=[O:40])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:43])=[N-:28]>>[N+:27](=[C:29]1[CH:38]=[C:37]([S:39]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]=[N+:24]=[N-:25])=[CH:19][CH:18]=2)(=[O:41])=[O:40])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:43])=[N-:28]
Reactant: [N-]=[N+]=Nc1ccc(OS(=O)(=O)c2cccc3c2C=CC(=[N+]=[N-])C3=O)cc1
Reactant: [N-]=[N+]=C1C=C(S(=O)(=O)Cl)c2ccccc2C1=O
Product: [N-]=[N+]=Nc1ccc(OS(=O)(=O)C2=CC(=[N+]=[N-])C(=O)c3ccccc32)cc1

Procedure:
This compound is prepared in a similar manner to Compound 1 but 2-diazo-1,2-dihydro-1-oxonaphthalene-4-sulfonyl chloride (2.2 grams) is used instead of the corresponding 5-sulfonyl chloride. The product is crystallized from ethanol. Yield of Compound 7 as a pure product is 1.1 gram, m.p. 131°-132°C (with decomposition).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][OH:20])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][O:20][S:37]([CH3:36])(=[O:39])=[O:38])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CO)no3)cc2)OC1(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Reaction time: 1 h

Procedure:
(4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-(3-(hydroxymethyl)isoxazol-5-yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (see US2004/0082553, page 67 (page 68 of pdf version)) (1000 mg, 2.45 mmol) in CH2Cl2 (25 mL) at 5° C. is treated with pyridine (0.23 mL, 2.95 mmol) and methanesulfonylchloride (0.19 mL, 2.45 mmol) then stirred for 1 hour, washed with saturated aqueous sodium bicarbonate, concentrated and used as is (1130 mg). m/z (Cl) 485 [M+H].
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:11]([OH:13])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:11]([N:3]([O:4][CH3:5])[CH3:2])=[O:13]
Reactant: COc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N(C)OC)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (5.37 g) was added to a mixture of 3-methoxy-4-(trifluoromethyl)benzoic acid (11.0 g), 1-hydroxybenzotriazole (6.76 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.59 g) and N,N-diisopropylethylamine (9.6 ml) in dichloromethane (200 ml), and the whole was stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with 25% of ethyl acetate in hexane as an eluent to give 3-methoxy-N-methoxy-N-methyl-4-(trifluoromethyl)-benzamide (12.0 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:15]([CH3:16])[C:3]=12.[C:24](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:16][C:15]1[C:3]2[C:2](=[O:1])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]([CH3:24])[C:4]=2[S:13][C:14]=1[CH2:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)c1cnc2sc(CN3CCOCC3)c(C)c2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.7 %

Procedure:
Ethyl 4-hydroxy-3-methyl-2-(morpholin-4-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate (Preparation 27, 1.47 g) and potassium carbonate (1.21 g) are suspended be in DMF (25 mL). The mixture is warmed until the ester dissolves and iodomethane (0.30 mL) is added. The reaction mixture is allowed to stir at room temperature for 20 h. The mixture is then poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (2×25 mL), dried (Na2SO4), and partially concentrated. Hexanes are added and the resulting solid is filtered to afford 0.70 g of the title compound as a light yellow solids Physical characteristics. M.p. 172-173° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.41, 4.19, 3.81, 3.65, 3.59, 2.48, 2.46, 1.27; MS (ESI+) m/z 351 (M+H)+. Anal. Found: C, 58.04; H, 6.54; N, 7.77; S, 8.97.