Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[OH:31][C:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:37]([C:36]1[C:32]([O:31][CH2:2][C:3]2[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=2)=[N:33][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=1)=[O:38]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.51 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.21 g), potassium carbonate (0.15 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (0.55 g, yield 86%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 157-158° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[CH2:8][CH:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=3[O:24]CC3C=CC=CC=3)[CH2:6][CH2:5][C:4]=2[N:3]=1>[Pd].C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[CH2:8][CH:7]([C:13]3[C:16]([C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:15][OH:24])[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Nc1nc(N)c2c(n1)CCC(Cc1cccc(C(F)(F)F)c1OCc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Product: Nc1nc(N)c2c(n1)CCC(c1c(CO)cccc1C(F)(F)F)C2

Procedure:
A mixture of 4.3 grams (0.010 mole) of 2,4-diamino-6-[(phenylmethoxy)(3-trifluoromethylphenyl)]methyl-5,6,7,8-tetrahydroquinazoline and a catalytic amount of 5% palladium on charcoal in 30 mL of ethanol is hydrogenated using a Parr hydrogenator. Upon completion of the uptake of the theoretical amount of hydrogen, the reaction mixture is filtered. The filtrate is concentrated under reduced pressure, yielding [(2,4-diamino-5,6,7,8-tetrahydroquinazolin-6-yl)(3-trifluoromethylphenyl)]methanol
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:20])[CH:3]=1
Reactant: Brc1cncc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Br)c2ccccc2c1
Reaction time: 18 h
Yield: 101.5 %

Procedure:
A solution of 4-bromoisoquinoline (4.16 g, 18.6 mmol) in chloroform (100 mL) was added dropwise over 1 h to a solution of 70% mCPBA (12.4 g, 50.3 mmol) in chloroform (100 mL) at rt. After stirring 18 h, the reaction mixture was washed with 1 N NaOH (2×150 mL), dried (MgSO4) and concentrated under reduced pressure to afford compound 13A (4.23 g, 94%) as an off-white solid. 1H NMR (400 MHz, CDCl3) □8.71 (s, 1H), 8.43 (s, 1H), 8.09 (d, 1H, J=8 Hz), 7.70 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[CH:7]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:14]=2[CH3:24])[CH:7]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: [3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[C:10]([O:17][CH3:18])(=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].C(Cl)Cl>O1CCOCC1.[Cu]Br>[CH3:15][O:14][C:12](=[O:13])[CH:11]([C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)[C:10]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC(=O)OC
Reactant: Clc1cc(Br)cc(Br)c1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)c1cc(Cl)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1,3-Dibromo-5-chlorobenzene (25 g, 93 mmol), dimethyl malonate (23.4 mL, 204 mmol), and copper(I) bromide (29.2 g, 204 mmol) were combined in 1,4-dioxane (300 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil; 8.2 g, 204 mmol) was added slowly, and the reaction was stirred at room temperature for 20 minutes, and then stirred at 105° C. for 4 hours. After cooling to room temperature, the mixture was worked-up with CH2Cl2 and aqueous Na4OH. The organic layer was concentrated, and the residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [P:1]([OH:5])([O-:4])([O-:3])=[O:2].[NH4+:6].[NH4+].N.[P:9](=[O:13])([OH:12])([OH:11])[OH:10]>>[P:1]([OH:5])([OH:4])([O-:3])=[O:2].[NH4+:6].[P:9]([OH:13])([O-:12])([O-:11])=[O:10].[NH4+:6].[NH4+:6]
Reactant: O=P(O)(O)O
Agent: N
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Product: O=P([O-])(O)O

Procedure:
The process of the invention enhances the production of a narrow range of granular diammonium phosphate particle size distribution comprising reacting anhydrous ammonia and aqueous phosphoric acid in a reactor to obtain a reaction product slurry of monoammonium phosphate and diammonium phosphate. The slurry is further reacted in a rotating drum granulator-reactor with anhydrous ammonia to yield a moisture containing diammonium phosphate. The moisture containing diammonium phosphate is introduced into a rotating drum dryer to remove the moisture from the diammonium phosphate resulting in a dried granular diammonium phosphate mixture. The dried solid granular diammonium phosphate is fed into a classifying means for separating into oversize, undersize and product granular diammonium phosphate. The oversize is milled and recycled along with the undersize obtained from the classifying means back to the granulator-reactor. The desired granular size is collected from the classifying means to be stored, packaged or shipped. The improvement of the conventional process comprises diverting a portion of the dried solid granular diammonium phosphate mixture after drying and prior to delivery of the dried solid granular diammonium phosphate to the classifying means and feeding the diverted portion to the granulator-reactor and setting the classifying means to a narrow size separation whereby a narrow range of the particle size distribution of granular diammonium phosphate produced is enhanced.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][CH:14]1[CH2:16][CH2:15]1.[OH-].[K+]>CCO>[CH:14]1([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15]1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: BrCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cccc(OCC2CC2)c1
Yield: 58.8 %

Procedure:
A mixture containing 2-(3-hydroxyphenyl)acetic acid (1.0 g, 6.6 mmol), (bromomethyl)cyclopropane (0.97 g, 7.2 mmol), potassium hydroxide (0.920 g, 16.4 mmol), KI (22 mg, 0.13 mmol) in EtOH (20 mL) was refluxed for 18 h. The solvent was removed in vacuo, and the residue was dissolved in 50 mL of water and extracted with ether. The aqueous layer was acidified with aqueous 1N HCl and extracted with EtOAc. The organic layers were dried (Na2SO4) and concentrated to afford a residue which was purified by silica gel chromatography (petroleum ether/EtOAc 4:1) to get 2-(3-(cyclopropylmethoxy)phenyl)acetic acid as a white solid (0.80 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:7]([CH:10]=1)[C:8]#[N:9].[CH3:17][N+:18]([CH3:20])=[CH2:19].[I-]>CN(C=O)C>[CH3:17][N:18]([CH2:20][C:15]1[N:11]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:10][C:7]=2[C:8]#[N:9])[CH:12]=[N:13][C:14]=1[CH3:16])[CH3:19]
Reactant: COc1ccc(-n2cnc(C)c2)c(C#N)c1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(-n2cnc(C)c2CN(C)C)c(C#N)c1
Yield: 83 %

Procedure:
As described for example 84b, 5-methoxy-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 16 h at 70° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as an oil (yield: 83%). MS: m/e=271.4 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[CH2:25](O)[CH3:26]>>[CH2:25]([O:11][C:6]12[O:1][CH:2]([C:8]([CH3:9])([CH3:10])[CH2:7]1)[CH:3]([O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH:4]=[C:5]2[CH3:12])[CH3:26]
Reactant: CC1=CC(OC(=O)c2ccc([N+](=O)[O-])cc2)C(O)C(C)(C)CC1=O
Reactant: CCO
Product: CCOC12CC(C)(C)C(O1)C(OC(=O)c1ccc([N+](=O)[O-])cc1)C=C2C
Yield: 64 %

Procedure:
5-Hydroxy-4-(4-nitrobenzoyloxy)-2,6,6-trimethyl-2-cyclohepten-1-one (1.00 g, 3.0 mM) obtained in Example 44 was treated with ethanol (20 ml) according to the procedures described in Example 99 and crystallized from a mixed solution of ethyl acetate and hexane to obtain 0.7 g (64%) of 1-ethoxy-4-(4-nitrobenzoyloxy)-2,6,6-trimethyl-8-oxabicyclo[3.2.1]oct-2-ene (AU246) as light yellow flakes. Melting point: 144° to 146° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][N:28]([CH3:36])[C:29](=[O:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][CH2:30][C:29]([N:28]([CH3:36])[CH3:27])=[O:35])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C(=O)CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CN(C)C(=O)CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (87 mg, 77%), MS (ISP) m/z=456.3 [(M+H)+], mp 205° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-(dimethylamino)-4-oxobutanoic acid.
Reaction SMILES: [CH2:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[CH2:4][CH:3]=[CH:2]1.O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][CH2:17][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:5]=2[CH2:4][CH:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2C3=C(CC=CC3)CCc3ccccc32)cc1
Reactant: C1CCNC1
Solvent: O
Product: C1=CCC2=C(C1)CCc1ccccc1C2CCN1CCCC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A suspension of 59.8 g of 2-(4,5,10,11-tetrahydro-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl-p-toluenesulfonate in 180 ml of pyrrolidine is stirred under argon at room temperature for 21 hours, subsequently poured into a mixture of ice and 300 ml of water and extracted twice with 1.2 l of distilled ether each time. The organic extracts are washed twice with 400 ml of water each time and a small amount of ice, combined, dried over magnesium sulfate and evaporated. The residue is taken up twice in 100 ml of dry toluene each time and the solutions obtained are in each case evaporated to dryness. There is obtained 1-[2-(4,5,10,11-tetrahydro-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine in the form of an oil which crystallizes upon standing; m.p. 56°-57°. By recrystallization from pentane there is obtained product of melting point 62°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[CH:26]=O)=[CH:18][CH:17]=1.[O:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=[C:32]2[O:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C/C=C/C=O)cc1
Reactant: O=C1COC(=O)N1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=CC=CC=C2OC(=O)NC2=O)cc1
Yield: 31 %

Procedure:
In substantially the same manner as in Example 1, (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadien-1-al was allowed to react with 2,4-oxazolidinedione to give 5-[5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadienylidene]-2,4-oxazolidinedione. The yield was 31%. Recrystallization from dichloromethane-methanol gave yellow needles, m.p.209°-211° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(N(CCCC)CCCC)CCC.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(Cl)cc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cl)cc1/C=C/C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
To a degassed solution of 1-(2-bromo-4-chlorophenyl)ethanone (1.0 g, 4.28 mmol), tributylamine (2.041 mL, 8.57 mmol), and tert-butyl acrylate (1.255 mL, 8.57 mmol) in DMF (10 mL) was added palladium on carbon (0.456 g, 0.428 mmol) and palladium (II) acetate (0.096 g, 0.428 mmol). The reaction mixture was warmed to 100° C. After 16 h, the reaction was cooled to rt and filtered. The solid was rinsed with DMF and the filtrate was diluted with EtOAc and washed with H2O (2×) followed by brine. The crude product was then dried over Na2SO4, filtered and concentrated. Purification by normal phase chromatography afforded Intermediate 4A (0.760 g, 63%), as a brown oil. MS (ESI) m/z: 225.0 (M-C4H8+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([O:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:36][N:37]=[CH:38]S(O)(=O)=O>CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([O:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH:38]=[N:37][NH2:36])[CH2:2][CH2:3]2)[CH:10]=1)(=[O:18])=[O:19]
Reactant: NN=CS(=O)(=O)O
Reactant: Cc1cc(OCC2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCC2CCN(C=NN)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Yield: 36.3 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-4-yl)methoxy]-5-methylphenyl ester (396 mg, 1.0 mmol), as prepared in the preceding step, in DMF (10 mL), N,N-diisopropylethylamine (0.5 mL) and aminoiminomethanesulfonic acid (248 mg, 2.0 mmol) was stirred at room temperature overnight. The DMF was removed in vacuo and the residue was purified by flash column chromatography (90:10 methylene chloride:methanol saturated with NH3) to give the title compound as a white foam (159 mg, 36%). 1H-NMR (300 MHz, CDCl3) δ 1.45 (m, 2H), 1.92 (m, 3H), 2.21 (s, 3H), 3.07 (t, 2H), 3.69 (d, 2H), 4.09 (d, 2H), 6.46 (d, 1H), 6.49 (s, 1H), 6.56 (s, 1H), 7.28 (s, 3H), 7.39 (t, 1H), 7.62 (m, 2H), 7.95 (dd, IH). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C20H24N3O4SCl: 438.1 (M+H), 460.1 (M+Na), Found: 438.3, 460.1.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[Na].[NH2:8][C:9]1[C:17]2[C:12](=[N:13][C:14]([N:21]3[CH2:30][CH2:29][C:24]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:23][CH2:22]3)=[CH:15][C:16]=2S(C)=O)[S:11][C:10]=1[C:31]([NH2:33])=[O:32]>O>[NH2:8][C:9]1[C:17]2[C:12](=[N:13][C:14]([N:21]3[CH2:22][CH2:23][C:24]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:29][CH2:30]3)=[CH:15][C:16]=2[O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[S:11][C:10]=1[C:31]([NH2:33])=[O:32]
Reactant: OCC(F)(F)F
Reactant: CS(=O)c1cc(N2CCC3(CC2)OCCO3)nc2sc(C(N)=O)c(N)c12
Agent: [Na]
Solvent: O
Product: NC(=O)c1sc2nc(N3CCC4(CC3)OCCO4)cc(OCC(F)(F)F)c2c1N
Temperature: 25 °C

Procedure:
To 30 mL of 2,2,2-trifluoroethanol cooled to 0° C. was added sodium metal (0.60 g, 15 mmol), cut fresh and washed in hexanes, in small portions. The mixture was allowed to warm up to room temperature and let stir until all of the sodium metal had reacted. To the mixture was added 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methanesulfinyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (1.30 g, 3.28 mmol) as a solid in one portion. The mixture was heated to 70° C. for 15 h. The mixture was cooled to room temperature and diluted with H2O. The mixture was washed with CH2Cl2 and the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.940 g of 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-(2,2,2-trifluoro-ethoxy)-thieno[2,3-b]pyridine-2-carboxylic acid amide as a white powder.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9].C(OCC)(=O)C>C1COCC1>[CH:10]1([C:8](=[O:9])[CH2:7][C:2](=[O:4])[CH3:1])[CH2:12][CH2:11]1
Reactant: CC(=O)C1CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CC(=O)C1CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a stirring solution of THF (100 mL) was added potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3.27 mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35° C., via addition funnel over a 25 min period. The contents were heated and stirred at 60° C. After 3 h, the contents were removed from heating, and allowed to cool to room temperature. The reaction mixture was carefully diluted with 30 mL 2 N HCl and stirred for 10 min. The mixture was extracted with diethyl ether (3×50 mL), and the combined organic layers washed with brine (1×50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (eluent: 0 to 15% EtOAc in hexanes) with good separation afforded 1-cyclopropyl-1,3-butanedione as a light yellow colored oil, 3.9 g in ˜75% purity (residual solvent), for an overall yield of 70%. 1H NMR (400 MHz, CDCl3) δ ppm 0.89-0.96 (m, 2 H), 1.09-1.15 (m, 2 H), 1.59-1.69 (m, 1H), 2.04 (s, 3H), 5.63 (s, 1 H), 15.5-16.0 (br s, 1H).
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=5)[N:33]=[CH:32][C:31]4=[O:42])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=5)[N:33]=[CH:32][C:31]4=[O:42])[CH2:26][CH2:27]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.5 mL of methanol solution containing 83 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, stirred at room temperature for 2 hours, and allowed to stand at the same temperature for 14 hours. Ethyl acetate was added, and the resulting solid was filtered to give 68 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one hydrochloride as a black solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br>C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2cccc(Br)c2)oc1C
Yield: 91.6 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (5.00 g, 52.0 mmol), commercial 3-bromobenzylbromide (13.0 g, 52.0 mmol) and 2.5M n-BuLi/hexanes (20.8 mL, 52.0 mmol) in THF. Purification on Biotage KP-Sil eluting with 1% EtOAc/pet. ether gave 12.63 g (85%) of the title compound. 1H NMR (DMSO-d6) δ1.85 (s, 3 H), 2.10 (s, 3 H), 3.86 (s, 2 H), 5.90 (s, .1 H), 7.21-7.30 (m, 2 H), 7.34-7.47 (m, 2 H).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:18])[N:33]([CH2:32][C:29]4[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(C(=O)OC)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-(aminomethyl)benzoic acid methyl ester (0.28 g, 1.4 mmol). Purification using silica gel, eluting with 4:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 110 as a white solid (m.p. 244-246° C.).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C=O)C>[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][C:2]2[CH:13]=[CH:12][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=3[CH:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: O=C1CCCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc3c(c2)C(=O)CCCC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
To 3-hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.76 g, 10.0 mmol) dissolved in DMF (10 ml) were added potassium carbonate (2.76 g, 20.0 mmol) and 4-methylbenzyl bromide (2.04 g, 11.0 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with water (20 ml) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 40 g, ethyl acetate/hexane=1/30). The objective fractions were concentrated under reduced pressure to obtain 3-(4-methylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.74 g, 9.77 mmol, 98%).