Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A mixture of methyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (610 mg), lithium hydroxide monohydrate (154 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, and 1N hydrochloric acid (3.7 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. Colorless crystals were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (583 mg, yield: 98%). This was recrystallized from ethyl acetate-hexane. Melting point: 152–153° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](N)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.N([O-])=O.[Na+].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([CH3:24])=[O:23]>O.C(#N)C.CCOCC>[CH3:24][C:22]([C:18]1[O:17][C:21]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1)=[O:23]
Reactant: CC(=O)c1ccco1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
A mixture of 200 g (1.16 mole) of p-aminophenyl methyl sulfone, 405 ml of concentrated hydrochloric acid, and 150 ml of water was heated at 80° for 20 minutes and then cooled to 0°. A solution of 80 g (1.16 mole) of sodium nitrite in 270 ml of water was added dropwise while maintaining the temperature between 0°-5° by means of an ice bath. The near solution was kept at 0° for 15 minutes. A solution of 129 g (1.16 mole) of methyl 2-furyl ketone in 125 ml of acetonitrile was added followed by a solution of 30 g of CuCl2 .2H2O in 100 ml of water. The reaction, after stirring in the cold for one hour, was allowed to warm to room temperature at which time it became exothermic and was controlled below 55° by means of an ice bath. The reaction, after stirring overnight at room temperature, was treated with 500 ml of ether with a solid forming. The solid was filtered, washed with dilute NaOH solution, and refluxed in acetonitrile with the insoluble material being removed by filtration. The filtrate was again heated to reflux and water was added to the "cloud point". Upon cooling an oil formed from which the acetonitrile was decanted. The acetonitrile was again treated with water and the resulting solid was filtered and recrystallized from ethyl acetate/charcoal and airdried to yield 28 g (9%) of 5-(p-methylsulfonylphenyl)-2-furyl methyl ketone. An analytical sample was prepared by drying a sample in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 160°-164°.
Reaction SMILES: CNCCN.C(OC([S:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=O)(C)(C)C>O1CCOCC1>[CH3:21][C:16]1[CH:17]=[C:18]([CH3:20])[N:19]=[C:14]([SH:13])[N:15]=1
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Agent: CNCCN
Solvent: C1COCCO1
Product: Cc1cc(C)nc(S)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-methyl-ethylenediamine (0.10 mol, 8.8 cm3) in dioxane (50 cm3), at room temperature and under a nitrogen atmosphere, was added a solution of S-tert-butyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (0.05 mol, 12 g) in dioxane (50 cm3), dropwise, over 3 h. After the addition was complete, the solution was stirred at room temperature for a further 15 h. The precipitate which formed (4, 6-dimethyl-2-mercaptopyrimidine) was removed from the solution, and the filtrate conc. in vacuo to half its original volume (50 cm3). To this residue, was added water (80 cm3) and the solution then left to stand at room temperature for 15 min. The bis-(t-BOC)-diamine precipitate was then removed, and the filtrate conc. in vacuo. To the residue was added water (80 cm3), and the solution subsequently saturated with sodium chloride. This saturated solution was extracted with ethyl acetate (4×40 cm3), and the organic extracts combined, dried (MgSO4), filtered, and conc. in vacuo to give an oil. This oil was dissolved in water (50 cm3) and acidified to pH 3 with 1M hydrochloric acid. The solution was then extracted with ethyl acetate (3×100 cm3). The aqueous layer was then collected, decolourized with activated charcoal and filtered over Celite. The filtrate was then conc. in vacuo . If necessary, fractional recystallization from room temperature methanol was used to separate the required product from any diamine dihydrochloride by-product. The filtrate was then conc. in vacuo. The product was isolated by trituration from hexane, to give a fine off-white solid which consisted of a mixture of N-t-BOC, N-methyl-ethylenediamine monohydrochloride and N-t-BOC, N′-methyl ethylenediamine monohydrochloride in a 4:1 ratio (4.8 g, 45%). m.p. 104-105° C. δH (400 MHz; methanol-d4) 3.52-3.37 (2H, t, J 4.8 Hz), CH2NH; 3.31 (2H, t, J 4.8Hz), CH2NH(CH3); 2.81 (3H, s), NCH3; 1.43 (9H, s), C(CH3)3. δC (75.4 MHz; methanol-d4) 157.88, C═O; 81.60 C(CH3)3; 47.47, CH2NH(CH3); 39.09, CH2NH; 28.65, C(CH3)3. Found: M+. 210.72.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.BrCCC1C=CC2C(=CC=CC=2)C=1>>[CH:10]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]=[CH:2][C:1]=1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]1
Reactant: O=C(NC1CCN(CCc2cccc3ccccc23)CC1)c1ccccc1
Agent: BrCCc1ccc2ccccc2c1
Product: O=C(NC1CCN(CCc2ccc3ccccc3c2)CC1)c1ccccc1

Procedure:
Prepared in a similar manner to the compound of Example 12 but using 2-(2-bromoethyl)-naphthalene in place of the 1-isomer. The product (m.p. 190°-3° C.) was crystallised from isopropanol. (Found: C, 80.5; H, 7.5; N, 7.7. C24H26N2O requires C, 80.4; H, 7.3; N, 7.8%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>CN(C)C=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:4][CH2:3][CH2:2][CH2:1][OH:5])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OCCCO
Reaction time: 2 h

Procedure:
To a stirred mixture of 30.4 parts of 1,3-propanediol and 90 parts of N,N-dimethylformamide were added 5.28 parts of a sodium hydride dispersion 50% at a temperature below 20° C. Stirring was continued for 2 hours at room temperature under nitrogen atmosphere. Then there were added dropwise 15.9 parts of 1,4-difluoro-2-nitrobenzene so that the temperature had been maintained below 30° C. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 21.5 parts 3-(4-fluoro-2-nitrophenoxy)propanol as a residue (intermediate 24).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.NC1C=C2C(=CC=1)C[C@]1(C3C(=NC=CC=3)NC1=O)C2>>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Product: O=Cc1ccc2cc3c(cc2n1)C[C@@]1(C3)C(=O)Nc2ncccc21

Procedure:
Essentially following the procedures described for Intermediate 6, but using (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (described in Intermediate 4) in place of (S)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, the title compound was obtained. MS: m/z=316 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23](=[O:30])[N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46].CNC>C(Cl)Cl.CO>[C:45]([N:27]1[CH2:26][CH2:25][N:24]([C:23](=[O:30])[C:22]([NH:21][C:18]23[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]2)[CH2:14][N:13]2[C:32](=[O:35])[C:33]([OH:34])=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:37][CH:36]=4)=[O:9])[N:11]=[C:12]32)=[O:31])[CH2:29][CH2:28]1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCNCC1
Agent: CNC
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)C(=O)NC23CCC(CC2)Cn2c3nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
To a solution of N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.049 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.034 mL, 0.244 mmol), followed by acetyl chloride (0.017 mL, 0.244 mmol) and the resulting mixture stirred at room temperature. After 16 h, the reaction mixture was concentrated to give crude product which was dissolved in methanol (2 mL) and treated with 2M dimethylamine in methanol (0.5 mL). The resulting reaction mixture was stirred at 60° C. for 2 h then cooled and purified by preparative HPLC to afford the title compound as a brown solid (13 mg, 46% yield). 1H NMR (500 MHz, CDCl3) δ: 12.05 (1 H, brs), 8.53 (1 H, brs), 8.48 (1 78, 5.65 Hz), 7.07 (2H, t, J=8.24 Hz), 4.66 (2 H, d, J=5.80 Hz), 4.24 (2 H, d, J=3.05 Hz), 4.18 (1 H, brs), 3.95-4.03 (1 H, m), 3.75 (2 H, brs), 3.46-3.63 (4 H, m), 2.64-2.73 (2 H, m), 2.51-2.58 (1 H, m), 2.11 (3 H, d, J=9.46 Hz), 1.95-2.14 (4 H, m), 1.76-1.82 (2 H, m). LCMS (M+H)=555.56. HPLC purity: >95%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:39])[N:14]([CH3:38])[C:15]([CH:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31]C)=[O:30])=[C:16]([C:17]3[C:18]([CH3:27])=[C:19]4[C:24](=[CH:25][CH:26]=3)[O:23][CH2:22][CH2:21][CH2:20]4)[C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[OH-].[Na+].Cl.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CI.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO.O>[C:34]([O:33][CH:28]([C:15]1[N:14]([CH3:38])[C:13](=[O:39])[C:12]2[N:8]([CH3:1])[CH:9]=[CH:10][C:11]=2[C:16]=1[C:17]1[C:18]([CH3:27])=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:29]([OH:31])=[O:30])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3C)ccc2c1CCCO2
Temperature: 70 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
A solution of methyl 2-(1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (40 mg, 0.076 mmol) in Tetrahydrofuran (THF) (0.2 mL), Methanol (0.200 mL), Water (0.200 mL) was treated with NaOH (24.21 mg, 0.605 mmol) and heated at 70° C. for 3 hours. The mixture was cooled to 0° C., treated with HCl (1M) until pH <2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resultant was dissolved in Tetrahydrofuran (THF) (0.2 mL), treated with KHMDS (0.757 mL, 0.378 mmol) and stirred at ambient temperature for one hour. Additional KHMDS (0.757 mL, 0.378 mmol) was added and the mixture was heated to 70° C. for 2 hours. The mixture was cooled to 0° C., treated with HCl (1M) until pH <2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resultant was dissolved in N,N-Dimethylformamide (DMF) (0.5 mL), treated with MeI (0.024 mL, 0.378 mmol) and potassium carbonate (52.3 mg, 0.378 mmol) and then stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resultant was dissolved in Tetrahydrofuran (THF) (0.2 mL), Methanol (0.200 mL) and Water (0.200 mL), treated with NaOH (24.21 mg, 0.605 mmol) and then heated to 70° C. for 3 hours. The mixture was cooled to 0° C., treated with HCl (1 M) until pH <2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to afford 2-(tert-butoxy)-2-(1,6-dimethyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid (6 mg, 0.013 mmol, 17.72% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.28-7.33 (m, 1H) 6.96-7.02 (m, 1H) 6.92-6.96 (m, 1H) 6.70-6.81 (m, 1H) 5.70-5.81 (m, 1H) 5.15-5.46 (m, 1H) 4.17-4.25 (m, 5H) 3.66-3.68 (m, 3H) 2.60-2.77 (m, 2H) 2.06-2.16 (m, 2H) 1.92-2.05 (m, 3H) 0.98-1.05 (m, 9H); LCMS (m/z) ES+=439 (M+1).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:8]([F:21])=[C:7]([NH:22]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1)C.OS(O)(=O)=O.CC#N>O>[NH2:22][C:7]1[CH:6]=[C:5]([CH:4]=[O:3])[N:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[C:8]=1[F:21]
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(-c2ccc(C(F)(F)F)nc2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: Nc1cc(C=O)nc(-c2ccc(C(F)(F)F)nc2)c1F
Yield: 43.1 %

Procedure:
Following the procedure of Example 12, 6-(diethoxymethyl)-3-fluoro-6′-(trifluoromethyl)-N-trityl-[2,3′-bipyridin]-4-amine (1203 mg, 2 mmol), conc H2SO4 (0.5 mL), CH3CN (25 mL) and H2O (25 mL) gave 4-amino-3-fluoro-6′-(trifluoromethyl)-[2,3′-bipyridine]-6-carbaldehyde (248 mg, 0.861 mmol, 43.0%) as a white solid: mp 166-167° C.; 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 9.35 (s, 1H), 8.54 (d, J=8.2 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.40 (d, J=6.5 Hz, 1H), 4.67 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 192.35, 149.96 (d, J=8.9 Hz), 149.50 (d, J=5.2 Hz), 149.03 (d, J=260.1 Hz), 145.2, 143.03 (d, J=12.4 Hz), 140.95, 137.48 (d, J=5.3 Hz), 133.55, 122.83, 120.25 (d, J=2.7 Hz), 108.70 (d, J=4.3 Hz); 19F NMR (376 MHz, CDCl3) δ −67.98, −142.26; HRMS-ESI (m/z) [M+H]+ calcd for C12H7F4N3O, 285.0525. found, 285.0525.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[CH:18][S:19][C:13]=2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11]1.O.Cl.[C:26]1([CH:36]=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCCC1>[OH:37][CH:36]([C:18]1[S:19][C:13]2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11][N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(C)Cc1nn(C)c(=O)c2ccsc12
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3cccc4ccccc34)sc12
Reaction time: 2 h

Procedure:
Lithium diisopropylamide (6.75 mmol) in tetrahydrofuran (8 ml) and 1-naphthaldehyde (0.7 ml) in tetrahydrofuran (5 ml) were added alternately to a solution of 5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (1 g) prepared in b) above in tetrahydrofuran (20 ml) at 0° C. After 2 hours, water (10 ml) was added, the reaction mixture was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The organic phase was washed once with dilute hydrochloric acid, twice with saturated sodium hydrogen carbonate solution and once with brine, before being dried and evaporated. Purification by chromatography eluting with isohexane/ethyl acetate (1:1), and subsequent HPLC eluting with the same gave the title compound (0.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14](C(O)=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.NCC(C1C=CC(Br)=CC=1)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 148.2 %

Procedure:
5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-tert-butyl ester (350 mg, 1.45 mmol) was mixed with HATU (551 mg, 1.45 mmol) in DMF (5 mL) and the mixture was stirred at room temperature for 30 minutes. 2-Amino-1-(4-bromo-phenyl)-ethanone bis HCl salt (416 mg, 1.45 mmol) in 2 mL DMF was added, followed by DIEA (3.5 eq., 0.88 mL) dropwise at 0° C. The reaction was stirred at 0° C. for 40 minutes. The reaction mixture was diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 642-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 67%). LCMS-ESI−: calc'd for C20H25BrN2O4: 437.33. Found: 460.1 (M+Na+). 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester: 15 mL Xylenes was added to 642-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 0.97 mmol) and ammonium acetate (20 eq., 1.5 g). The mixture was heated in microwave at 140° C. for 60 minutes. The mixture was diluted with EtOAc and washed with sat.NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (249 mg, yield 61%). LCMS-ESI−: calc'd for C20H24BrN3O2: 418.33. Found: 418. (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Yield: 34 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.23 g, 1.0 mmol), sodium hydride (60% in oil, 0.048 g, 1.2 mmol) and 1-iodopentane (0.26 mL, 2.0 mmol) to give the title compound (0.105 g) as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][CH:13]=O)[CH2:9]1)=O)(C)(C)C.[CH3:15][C:16]1N(CC2C=CC(NN)=CC=2)C=CN=1.C([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O>[NH:8]1[C:11]2[C:10](=[CH:12][CH:13]=[CH:15][CH:16]=2)[CH:9]=[CH:6]1
Reactant: Cc1nccn1Cc1ccc(NN)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CC=O)C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 105.1 %

Procedure:
N-tert-Butyloxycarbonyl-3-formylmethylazetidine (0.3 g, 1.51 mmol) was added to a solution of 4-(2-methylimidazol-1-ylmethyl)phenylhydrazine (0.36 g, 1.51 mmol) in 4% H2SO4 (25 ml) and the resulting solution refluxed for 3h. The mixture was then cooled to room temperature, basified with K2CO3 and extracted with n-butanol (2×100 ml). The combined extracts were dried (MgSO4), evaporated, and the residue chromatographed through silica-gel eluting with CH2Cl2 /MeOH/NH3 (20:8:1) to give the title-indole (0.186 g, 46%), mp 88°-90° C.; δ (250 MHz, CD3OD) 2.02 (3H, s, CH3), 3.76-3.86 (4H, m, 2 of CH2), 4.04-4.20 (1H, m, CH of azetidine), 5.06 (2H, s, CH2), 6.70 (1H, d, J=1.4 Hz, Ar--H), 6.82 (1H, dd, J=1.5 and 8.4 Hz, Ar--H), 6.90 (1H, d, J=1.4 Hz, Ar--H), 7.12 (1H, s, Ar--H), 7.23 (1H, d, J =8.4Hz, At-H), 7.26 (1H, d, J =1.5Hz, Ar--H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[CH2:34][OH:35]>>[F:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][C:30]2[CH:31]=[CH:32][C:33]([CH2:34][OH:35])=[C:28]([F:27])[CH:29]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:2])=[O:26])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: OCc1ccc(B(O)O)cc1F
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(CO)c(F)c5)ccc(F)c43)ccc21

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-fluoro-4-hydroxymethyl-phenylboronic acid following a procedure analogous to that described for Intermediate 6. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 6): tR=1.02 min; Mass spectrum (ESI−): m/z=467 [M−H]−.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[C:11](=[O:20])[N:12]([CH3:19])[C:13](=[O:18])[N:14]([CH3:17])[C:15]=1[NH2:16]>CN(C)C1C=CC=CC=1>[N:12]1([C:11](=[O:20])[C:10]2[NH:9][C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[N:16][C:15]=2[N:14]([CH3:17])[C:13]1=[O:18])[CH3:19]
Reactant: O=C1CCCC(=O)O1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: CN(C)c1ccccc1
Product: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O

Procedure:
A mixture of 31.3 g glutaric anhydride, 25 g 5.6-diamino-1,3-dimethyl uracil, and 300 ml N,N-dimethyl-aniline was heated under reflux for 4 hours. Upon cooling, the product crystallized from the dark, clear reaction mixture. The crystals were collected by filtration, washed with benzene, then with methanol, and dried affording 187 g light yellow solid.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=3[Cl:27])=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:27][C:20]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:18]([NH:17][CH2:16][C:15]1[CH:29]=[CH:30][C:12]([C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH:11]=2)=[CH:13][CH:14]=1)=[O:28]
Reactant: CC(C)(C)Oc1cc(-c2ccc(CNC(=O)c3c(F)ccc(F)c3Cl)cc2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(-c2cc[nH]c(=O)c2)cc1)c1c(F)ccc(F)c1Cl

Procedure:
The compound N-(4-(2-tert-butoxypyridin-4-yl)benzyl)-2-chloro-3,6-difluorobenzamide was re-dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuum and then purified by reverse phase chromatography to afford 2-chloro-3,6-difluoro-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide.