Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]3=[O:30].[C-]#N.[Na+].[CH3:36][N:37]1CCCC1=O>C(OCC)(=O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[C:18]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]#[N:37])=[CH:3][C:4]=4[O:32][CH2:31]3)[C:9]2=[O:30])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(Br)ccc12
Reactant: CN1CCCC1=O
Agent: Cl[Ni]Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 100 %

Procedure:
A 10 mL microwave reaction vessel was charged with 6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.51 g, 1.1 mmol), nickel chloride hexahydrate (0.25 g, 1.1 mmol), sodium cyanide (0.10 g, 2.1 mmol) and 1-methyl-2-pyrrolidinone (1 mL). The solution was irradiated at 200° C. for 20 min in a microwave reactor. The solution was allowed to cool to ambient temperature, diluted with ethyl acetate (25 mL) and filtered. The filtrate was washed with brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes to afford 1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile (0.50 g, 100%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.44-7.22 (m, 10H), 7.21-7.18 (m, 1H), 7.14-6.93 (m, 5H), 6.72 (d, J=7.8 Hz, 1H), 6.55 (d, J=7.5 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.80 (d, J=9.2 Hz, 1H).
Reaction SMILES: [C:1]([CH:4]([C:11](=O)[CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([CH3:12])[NH:16][N:15]=1
Reactant: NN
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1c(C)n[nH]c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of ethyl 3-acetyl-4-oxopentanoate (synthesized as described D. P. Shrout and D. A. Lightner, Synth. Commun. 20 (1990), 2075) (9.676 g, 51.96 mmol) in ethanol, at 0° C., was added slowly a solution of hydrazine hydrate (2.990 g, 59.75 g) in absolute ethanol. The reaction mixture was warmed to room temperature and stirred for 2 hours. After removing ethanol under vacuum, dichloromethane and water were added to the crude product and the organic layer was separated. The aqueous layer was extracted further with dichloromethane and the combined organic extracts were washed with water. After drying over MgSO4 and evaporation of the solvent under reduced pressure, the pyrazole was isolated as a yellow oil. Yield: 72% (6.777 g, 37.2 mmol).
Reaction SMILES: [C:1]([N:4]1[CH:11]=[C:10]([F:12])[C:8](=[O:9])[NH:7][C:5]1=[O:6])(=[O:3])[CH3:2].[H-].[Na+].Br[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:17]1.O>CN(C=O)C>[C:1]([N:4]1[CH:11]=[C:10]([F:12])[C:8](=[O:9])[N:7]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18](=[O:19])[O:17]2)[C:5]1=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc(F)c(=O)[nH]c1=O
Reactant: O=C1OC(Br)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)n1cc(F)c(=O)n(C2OC(=O)c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
In 8 ml of DMF was dissolved 3.44 g of 1-acetyl-5-fluorouracil and 0.80 g of sodium hydride (60% content) was added to the stirred solution mentioned above under ice cooling. Then, a solution of 4.69 g of 3-bromophthalide in 7 ml of DMF was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for 3.5 hours at room temperature. Then, 100 ml of water was added to the mixture and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate and then, the solvent was distilled off. The residue was washed twice with 25 ml each of n-hexane to obtain crude N1 -acetyl-N3 -phthalidyl-5-fluorouracil. To this product were added 50 ml of 0.05N hydrochloric acid and 50 ml of ethanol and the mixture was refluxed for 15 minutes. After the solvent was distilled off, water was added to the residue and the colorless crystal produced was collected by filtration. After washing with water and drying, the product was heated with 15 ml of chloroform under reflux for 3 minutes. After filtration while hot, there was obtained 2.65 g (50%) of colorless crystal. This was recrystallized from methanol to obtain colorless needles having a melting point of 234°-237°.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(CNc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Yield: 55.1 %

Procedure:
A mixture of 500 mg of 4-(4-chloroanilinomethyl)phenol, 632 mg of ethyl 2-bromo-2-methylpropionate, 7.5 ml of methyl isobutyl ketone and 448 mg of potassium carbonate is refluxed under heating for 6 hours. The insolubles are filtered off from the reaction mixture, and the filtrate is washed with water, dried and concentrated. The residue (730 mg) is purified by column chromatography, using 22 g of silica gel and chloroform as a developer to give 410 mg of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate, mp 58° to 60° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c3ncoc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (30 mg, 0.07 mmol) in CH2Cl2 (3 mL) was added triethylamine (22 mg, 0.22 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (16 mg, 0.11 mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (40 mg, 100% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H), 7.05, (m, 1H), 3.40 (m, 1H), 1.71 (m, 2H), 0.91-0.85 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31](Cl)[N:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31]([NH:25][C@H:23]([C:14]2[N:13]([C@H:11]3[CH2:12][C@H:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:10]3)[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=2)[CH3:24])[N:30]=[CH:29][N:28]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 90 °C

Procedure:
A mixture of (S)-1-[1-(trans-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (67 mg, 0.20 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (31 mg, 0.20 mmol) and DIPEA (0.18 mL, 0.99 mmol) in IPA (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM then MeOH and then 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford the title compound as a colourless glassy solid (60 mg, 67%). LCMS (Method B): RT 3.09 min [M+H]+ 458
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CC(C)=O>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:20]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(OCc2ccc(F)cc2F)c1
Temperature: 25 °C

Procedure:
To a solution of compound 4a (0.56 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and 2,4-difluorobenzyl bromide (0.56 mL, 4.4 mmol) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([C:15]1[CH2:16][C:17]2[C:22]([C:23]=1[N:24]1CCCC1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=O.Cl.[NH2:30]N.O>CCO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:30][N:24]=[C:23]2[C:22]3[C:17]([CH2:16][C:15]=12)=[CH:18][CH:19]=[CH:20][CH:21]=3
Reactant: NN
Reactant: Cc1onc(-c2ccccc2)c1C(=O)C1=C(N2CCCC2)c2ccccc2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1[nH]nc2c1Cc1ccccc1-2
Temperature: 80 °C

Procedure:
The compound from step b) was dissolved in EtOH (30 ml) and treated with hydrazine monohydrochloride (1.0 g, 13.3 mmol). The reaction vessel was fitted with an air-cooled condenser and heated to 80° C. for 36 h. The reaction mixture was cooled, water (10 ml) added, and the ethanol removed in vacuo. The residue was partitioned between EtOAc and water and the organic layer washed with water (2×). The organic layer was dried over MgSO4, evaporated, and the residue purified on alumina (Grade III), eluting with 0.5% EtOH/CH2Cl2 to obtain the title compound as a white solid (20.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.72 (brs, 1H), 7.52 (d, J=7.6 Hz, 2H), 7.43–7.34 (m, 5H), 7.28 (t, J=9.6 Hz, 2H), 3.3 (brs, 2H), 2.56 (s, 3H), m/z (ES+) 314 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH:13]([N+:16]([O-])=O)[CH2:14][CH3:15])[CH2:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni].O>[NH2:16][CH:13]([CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[C:8](=[O:19])[CH2:9]1)[CH2:14][CH3:15]
Reactant: CCC(C1CCN(Cc2ccc(F)cc2)C(=O)C1)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CCC(N)C1CCN(Cc2ccc(F)cc2)C(=O)C1
Reaction time: 24 h

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(1-nitropropyl)piperidin-2-one (2.8 g, 9.51 mmol) in ethanol (50 mL) was added Raney Nickel (2 grams of a 50% by weight slurry in water). The reaction mixture was shaken under 55 psi of hydrogen. After 24 hours, the reaction mixture was filtered through a bed a celite, then concentrated under vacuum to afford the title compound as a mixture of diastereomers. The first diastereomer has a retention time of 2.05 min and the second diastereomer has a retention time of 2.10 min. The HPLC method was performed on a Hewlett-Packard Zorbax SB-C8 column (75×4.6 mm, 3.5 micron) eluting with 5%-100% CH3CN (0.1% TFA) in H2O (0.1% TFA). ES MS M+1=265.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[O:29][C:30]([CH3:34])=[C:31]([CH3:33])[N:32]=1>ClC(Cl)(Cl)Cl>[Br:1][CH2:34][C:30]1[O:29][C:28]([CH3:27])=[N:32][C:31]=1[CH3:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C)c(C)o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(C)c(CBr)o1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a mixture of 795 parts of dry tetrachloromethane, 40.1 parts of N-bromosuccinimide and a few parts of benzoylperoxide there were added 25 parts of 2,4,5-trimethyloxazole under a nitrogen atmosphere. The whole was stirred for 1 hour at reflux temperature. After cooling in an ice/salt bath, the reaction mixture was filtered and the filtrate was evaporated, yielding 42.7 parts (99.9%) of 5-(bromomethyl)-2,4-dimethyloxazole (interm. 9).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:27]([NH2:29])=[O:28])[CH:8]=1)[CH2:2]2.C1C[O:33]CC1>O>[OH:6][CH:1]1[CH:5]([OH:33])[CH2:4][N:3]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:27]([NH2:29])=[O:28])[CH:8]=2)[CH2:2]1
Reactant: NC(=O)c1cc(N2CC3OC3C2)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(N2CC(O)C(O)C2)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a suspension of the 6-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide (0.050 g, 0.13 mmol) in THF (5 mL) and water (1 mL) was added a 60% HClO4 solution (0.1 mL). After stirring overnight, the reaction was heated at 50° C. for 2 days. After the reaction cooled it was quenched with solid NaHCO3 and evaporated in vacuo. The residue was chromatographed over silica gel with 50-100% acetone in hexanes. The product fractions were evaporated and the resulting residue dissolved in 1 mL acetonitrile with warming. Upon cooling a solid formed. The solid was filtered and rinsed once with 1 mL acetonitrile. The remaining solid was suspended in 1 mL warm acetonitrile, filtered and air-dried to give 6-(3,4-dihydroxypyrrolidin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a fine crystalline powder (0.009 g, 0.02 mmol, 17%). 1H NMR (400 MHz, DMSO-d6): 8.55 (2H, d, J=8.8 Hz), 8.34 (1H, d, J=2.4 Hz), 7.88 (1H, d, J=2.4 Hz), 7.31-7.24 (2H, m), 7.19-7.13 (2H, m), 7.05 (2H, d, J=9.0 Hz), 6.90 (1H, s), 5.29 (1H, d, J=3.7 Hz), 5.22 (1H, d, J=3.3 Hz), 4.14-4.10 (1H, m), 4.09-4.05 (1H, m), 3.76-3.63 (3H, m), 3.35-3.30 (1H, m). LC/MS: m/z=411.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][CH:16]3[CH:21]([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:23])=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[N:47]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49][CH2:48]1.Cl>O1CCCC1>[N:47]1([S:51]([NH:54][C:9](=[O:10])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[C:5]([O:14][CH2:15][CH:16]3[CH:21]([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:23])=[CH:6][C:7]=2[F:13])(=[O:53])=[O:52])[CH2:50][CH2:49][CH2:48]1
Reactant: CC1CCCC(C)C1COc1cc(F)c(C(=O)O)cc1C1CC1
Reactant: NS(=O)(=O)N1CCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CCCC(C)C1COc1cc(F)c(C(=O)NS(=O)(=O)N2CCC2)cc1C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a stirred solution of 5-cyclopropyl-4-((2,6-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid (0.07 g, 0.22 mmol) in tetrahydrofuran (2 mL) and under an atmosphere of nitrogen was added carbonyldiimidazole (0.053 g, 0.33 mmol) and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled down to ambient temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL, 0.45 mmol) was added followed by azetidine-1-sulfonamide (0.051 g, 0.37 mmol) and the stirring continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and directly purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.022 g, 22%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.75-8.55 (m, 1H), 7.57 (d, J=9.1 Hz, 1H), 6.62 (d, J=14.5 Hz, 1H), 4.23 (t, J=7.7 Hz, 4H), 4.01 (d, J=4.5 Hz, 2H), 2.35-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.86-0.56 (m, 20H); MS (ES+) m/z 439.1 (M+1); MS (ES−) m/z 437.2 (M−1).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=CC=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[F:35])[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC1CCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3F)c2ncn1C1CCC1
Yield: 91.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), cyclobutylamine (0.065 ml, 0.76 mmol), and acetic acid (0.1 ml) were used to give 110.2 mg (0.37 mmol, 91.7% yield) of the title compound.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(CC)CC)C.O[CH2:24][C:25]1([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)C>[C:31]1(=[O:32])[C:25]2([CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH2:24][O:33]1
Reactant: O=C(O)C1(CO)CCOCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1OCC12CCOCC2
Temperature: 0 °C
Reaction time: 20 h
Yield: 119.3 %

Procedure:
Trifluoromethanesulfonic anhydride (11.1 mL, 66.2 mmol), followed by triethylamine (17.8 mL, 127.4 mmol) was added to a slurry of 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid (10.20 g, 63.68 mmol) in anhydrous diethyl ether cooled to 0° C. (115 mL). The biphasic solution was stirred for 20 hours, warmed to room temperature, stirred an additional 2 hours. The layers were separated by decantation, and the lower layer diluted with 2% aqueous sodium bicarbonate solution (50 mL) and extracted with methylene chloride (4×200 mL). The combined organic extracts were washed with additional 2% aqueous sodium bicarbonate (100 mL), dried over magnesium sulfate, and concentrated in vacuo to afford 2,7-dioxaspiro[3.5]nonane-1-one as a pale yellow oil (10.8 g). IR (KBr) 1821 cm-1 ; 1HNMR (CD3Cl3) δ 1.92 (ddd, J=13.4, 8.1, 4.0 Hz, 2H) , 2.10 (dddd, J=13.4, 6.1,3.4, 0.8 Hz, 2H), 3.70 (ddd, J=11.8, 6.3, 3.9 Hz, 2H), 3.92 (ddd, J=11.8, 7.9, 3.4 Hz, 2H), 4.15 (s, 2H); 13CNMR (CD3Cl3) δ 30.78 (t), 55.78 (s), 64,46 (t), 71.50 (t), 173.42 (s), MS(EI) m/e=142. MS(CI) M+=H m/e=143, M++HNH4 m/e=160.
Reaction SMILES: C(O)C.[O:4]=[C:5]1[CH:11]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][CH2:9][C:8]2[CH:23]=[CH:24][CH:25]=[CH:26][C:7]=2[N:6]1[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].O.NN>>[NH2:12][CH:11]1[CH2:10][CH2:9][C:8]2[CH:23]=[CH:24][CH:25]=[CH:26][C:7]=2[N:6]([CH2:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:5]1=[O:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Yield: 86.9 %

Procedure:
To 100 mol of ethanol is added 10 g of tert-butyl 2-oxo-3-phthalimido-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate, and 5 g of hydrazine hydrate is added to the mixture, followed by refluxing for 2 hours. The reaction mixture is concentrated under reduced pressure, and 300 ml of water is added to the residue, followed by extraction with 200 ml of ethyl acetate. The extract is washed with 1N aqueous sodium hydroxide and water, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals, which separate out, are treated with a mixture of ether and petroleum ether and collected by filtration to give 6 g of tert-butyl 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as colorless prisms. m.p. 121°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:10][CH:8]([CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])(=[O:23])=[O:22]
Reactant: CC(O)COc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(COc1ccc(Cl)cc1)OS(C)(=O)=O
Temperature: -8 °C
Reaction time: 1 h

Procedure:
To a solution of 37.4 g of 3-(p-chlorophenoxy)propan-2-ol and 41 ml of triethylamine in 500 ml of dichloromethane stirred and chilled at -8° C. is added dropwise 18.7 ml of methanesulfonyl chloride in 50 ml of dichloromethane. After stirring at -8° C. for 1 hour, the solution is washed with 350 ml portions of ice cold water, 1N HCl, saturated NaCl, saturated NaHCO3 and saturated NaCl. The organic layer is dried (MgSO4) and the solvent removed under reduced pressure to give 54 g of product as white crystals, mp 72°-78° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=O.C>C(O)C>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[N:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:16]=[CH:17][C:18]=1[OH:19]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5.30 g (40 mmol) of (t-butoxycarbonyl)hydrazine in 40 ml of 80% aqueous ethanol was added a solution of 5.52 g of 3,4-dihydroxybenzaldehyde in 40 ml of the same solvent. After stirring for three hours at room temperature, the mixture was clarified with charcoal, filtered and the filtrate evaporated in vacuo. The residue was triturated with petroleum ether, filtered off by suction and dried in vacuo; yield: 8.5 g.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:10][C:9]1[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: C1COCCN1
Reactant: O=Cc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccc(F)c1N1CCOCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A 100 mL round-bottom flask was charged with 2,3-difluorobenzaldehyde (2.00 g, 14.1 mmol, 1.00 equiv), morpholine (1.84 g, 21.1 mmol, 1.50 equiv), potassium carbonate (4.90 g, 35.4 mmol, 2.52 equiv), and dimethyl sulfoxide (20 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (50 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/20) to yield 0.840 g (28% yield) of 3-fluoro-2-(morpholin-4-yl)benzaldehyde as a yellow solid. 1H NMR 300 MHz, (CDCl3) δ 10.54 (s, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.18-7.34 (m, 2H), 3.85 (br, 4H), 3.23 (br, 4H). LCMS (ESI, m/z): 210 [M+H].