Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:13][S:12](=[O:29])(=[O:28])[CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[CH2:32]([NH:35][NH2:36])[CH2:33][CH3:34]>CO>[CH2:32]([N:35]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:4]=2)[CH:10]2[CH2:11][S:12](=[O:29])(=[O:28])[CH2:13][C:14](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:15]2=[N:36]1)[CH2:33][CH3:34]
Reactant: O=C1C(=Cc2cccc(C(F)(F)F)c2)CS(=O)(=O)CC1=Cc1cccc(C(F)(F)F)c1
Reactant: CCCNN
Solvent: CO
Product: CCCN1N=C2C(=Cc3cccc(C(F)(F)F)c3)CS(=O)(=O)CC2C1c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 2.5g of tetrahydro-3,5-bis[[3-(trifluoromethyl)phenyl]methylene]-4H-thiopyran-4-one-1,1-dioxide and n-propyl hydrazine in 100ml of methanol is heated at reflux temperature for 1 hour. The crystals obtained on cooling to 5°-10°C are collected and dried in vacuo over phorphorus pentoxide at 50°C to yield 1.7g of the title compound, melting point 190°-191°C. The filtrate is diluted with water giving additional crude material which is recrystallized from methanol to give 400mg of the title compound, melting point 191°-193.5°C.
Reaction SMILES: [ClH:1].[C:2]1([CH3:14])[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH2:18]=O>C(O)=O>[ClH:1].[CH3:18][N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:14])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1
Reactant: Cc1ccc(C23CNCC2C3)cc1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: Cc1ccc(C23CC2CN(C)C3)cc1

Procedure:
A mixture of 4.19 g. of 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride and 20 ml. of water is made basic with sodium hydroxide. This mixture is extracted with ether and the ether is evaporated to give an oil. This oil is combined with 40 ml. of 97% formic acid and 35 ml. of 37% formaldehyde and the solution is heated on a steam bath for 2 hours. The solution is cooled, made basic with sodium hydroxide and extracted with ether. The extract is dried over magnesium sulfate, filtered, and the filtrate is saturated with hydrogen chloride. The precipitated crystals are collected and recrystallized from isopropyl alcohol to give 3-methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 197°-198° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:26])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].C1COCC1.O.[OH-].[Li+]>O>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=2)=[O:26])=[CH:15][CH:16]=1
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ncccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(COc1ccc(-c2ncccn2)cc1)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (41 mg) in a 1:1 mixture of THF and water (2.25 mL) was added lithium hydroxide monohydrate and the reaction mixture was stirred for 20 hours at room temperature. After such time the THF was evaporated off in vacuo and the remaining aqueous phase was neutralized by addition of a 1N HCl solution. The resulting precipitate was then isolated by filtration, washed with water, and dried in vacuo to yield the title compound as a light yellow solid. MS (m/e): 354.1 (M+H−).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[OH:13][C:14]1[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:23][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH3:22])[C:14]=1[O:13][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)[CH:18]=[O:19]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
0.5M solution of 1-bromomethyl-4-trifluoromethyl-benzene (1.9 g, 8.0 mmol) in DMF was added dropwise to a suspension of 4-hydroxy-3,5-dimethyl-benzaldehyde (930 mg, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (120 mg, 0.73 mmol) in DMF (100 ml). The reaction mixture was stirred at 90° C. overnight. After cooling, the solid residue was filtered off and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate and the organic layer washed twice with NaOH 1M, dried over Na2SO4 and evaporated to dryness. The residue was purified on silica gel, obtaining 2.24 g of the title compound in a quantitative yield.
Reaction SMILES: O[CH:2]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].C(Br)(Br)(Br)[Br:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[Br:26][CH:2]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCC#CC(O)CCCCC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCC#CC(Br)CCCCC(=O)OC

Procedure:
This compound was prepared by reaction of methyl 6-(±)-hydroxy-7-eicosynoate (preparative example V) with CBr4 /Ph3P reagent in exactly the same manner as described in preparative example VIII.
Reaction SMILES: C([O:4][C:5]1[C:18]2[CH:17]([CH3:19])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[O:10][C:9]=2[CH:8]=[C:7]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:28][CH:20]([C:7]1[CH:6]=[C:5]([OH:4])[C:18]2[CH:17]([CH3:19])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[O:10][C:9]=2[CH:8]=1)[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC1=C(CCCC1)C2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCCC1)C2C

Procedure:
1-Acetoxy-3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydro-9-methylxanthene is refluxed with potassium carbonate in 100 ml. of 15% aqueous methanol for 15 minutes. The reaction mixture is diluted with cold water and extracted with hexane. The organic phase is washed with water, dried (Na2SO4) and concentrated in vacuo to give a residue which, upon distillation, gives 3-(1,2-dimethylheptyl)-5,6,7,8,-tetrahydro-1-hydroxy-9-methylxanthene.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=2)[C@H:10]1[CH2:24][CH3:25])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[CH:16]=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@@H:9]([OH:8])[C@@H:10]2[CH2:24][CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chlorobenzonitrile (366 mg) in tetrahydrofuran (5 mL)-methanol (5 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless solid (yield: 221.2 mg, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:13][C:10]=1/[CH:11]=[CH:10]/[C:9](=[O:8])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(C=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1ccc(/C=C/C(C)=O)c(OCc2ccccc2)c1
Reaction time: 24 h
Yield: 147.6 %

Procedure:
A solution of 2-benzyloxy-4-(1,1-dimethylheptyl)benzaldehyde (65.2 g, 0.193 mole) and of 1-triphenylphosphoranylidene-2-propane (62.0 g, 0.195 mole) in dichloromethane (195 ml) was heated at reflux for 20 hours. Another portion of 15.5 g ylid (15.5 g, 0.047 mole) was added and heating at reflux continued for 24 hours. The reaction mixture was cooled, evaporated and diluted with ether. The resulting precipitate of triphenylphosphine oxide was removed by filtration. The crude oil was purified via column chromatography on 1.5 kg of silica gel eluted with 20% etherhexane to yield 53.9 g (74%) of the title compound as an oil.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[C:21]2[C:22]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[C:23]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])[O:27][C:26]([CH3:35])([CH3:34])[CH2:25][C:24]3=[O:36])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O>ClCCl>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([F:7])[C:21]2[C:22]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[C:23]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:32])[CH3:33])[O:27][C:26]([CH3:35])([CH3:34])[CH2:25][C:24]3=[O:36])=[CH:16][CH:15]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Reaction time: 2.5 h

Procedure:
At −78° C., a solution of 46 μl (350 μmol) of diethylaminosulfur trifluoride in 1 ml of dichloromethane is slowly added dropwise to a solution of 150 mg (320 μmol) of rac-6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 27A) in 4.5 ml of dichloromethane, and the mixture is stirred at this temperature for 2.5 h. The mixture is then allowed to thaw slowly to −15° C. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1→5:1) gives the target compound.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39]CC)=[O:38])=[CH:33][C:32]=2[I:42])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>C(O)C.[OH-].[K+].O>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:32]=2[I:42])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(N(CC(C)C)C[C@H](O)COc3cccc4[nH]c5ccccc5c34)cc2)c(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccc(C(=O)O)cc2I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.3 %

Procedure:
(S)-4-[2-hydroxy-3-([4-(4-carboethoxy-2-iodophenoxy)phenyl]-2-methylpropylamino)propoxy]carbazole (386 mg, 0.54 mmol) was dissolved in a mixture of ethanol (20 ml) and aqueous potassium hydroxide (20 ml, 5.ON) and was stirred at ambient temperature for 16 hours. The crude reaction mixture was concentrated in vacuo and the residue acidified with 5.0N HCl. The solution was allowed to stir for one hour at 0° C. and then concentrated in vacuo to afford a white solid. The residue was suspended in water and filtered, and the solids washed with cold water. The solids were triturated with pentane and dried to afford product as a white solid (370 mg, 100%). NMR, MS, IR, HPLC
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:25][C:26]1[C:31]([NH:32][CH3:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH2:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([F:25])=[C:31]([NH:32][CH3:33])[CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:24])[C:13]2=[O:23])[C:16]([CH3:22])=[N:17]1)[CH3:21]
Reactant: CNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1F
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(F)c(NC)c5)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 0.078 mmol) and [2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methyl-amine (stage 150.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.53 min (Method A); M+H=485 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.16 (s, 1H), 8.11-8.07 (m, 1H), 7.95-7.90 (m, 1H), 7.53-7.51 (m, 1H), 7.42-7.39 (m, 1H), 7.01-6.97 (m, 1H), 6.08 (q, br, 1H), 4.15 (q, 2H), 3.58 (s, 3H), 2.80 (d, 3H), 1.97 (s, 3H), 1.37 (t, 3H))
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2
Reactant: CC(C)(C=O)c1cc(F)c2c(=O)[nH]ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CO)c1cc(F)c2c(=O)[nH]ccc2c1
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
2-(8-Fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanal (137 mg, 587 μmol) was dissolved in MeOH and cooled in an ice bath. To the resulting solution was added NaBH4 (33 mg, 881 μmol) in one portion. The reaction mixture was stirred vigorously for 5 minutes before removing the cooling bath and stirring for 30 minutes. To the reaction mixture was added about 40 ml of 10% HCl and 40 ml EtOAc. The mixture was shaken and the EtOAc phase collected. The organic phase was washed with an equal volume of water. The aqueous phase was back extracted with 2×30 ml EtOAc. The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford 109 mg of a off-white powder. (M+H)+=236 m/e.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[O:11][C:10]1=[O:17])=O)(C)(C)C.[ClH:18]>CCOC(C)=O>[ClH:18].[NH2:8][C@H:9]1[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[O:11][C:10]1=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(C)(C)OC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)CC[C@H](N)C(=O)O1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
3(S)-(t-Butoxycarbonyl)amino-6,6-dimethyl-tetrahydropyran-2-one (0.36 g, 1.48 mmol) was dissolved in EtOAc (30 mL) and treated with HCl gas at -50° C. for 20 min and stirred at -30° to -50° C. for 20 min. Argon was bubbled into the soln for 10 min, then the soln was concentrated to give 0.265 g (100%) of the title compound as a white solid. 1H NMR (CD3OD) δ4.05-4.15 (m, 1H), 2.2-2.32 (m, 1H), 2.0-2.15 (m, 3H), 1.48 (s, 3H), 1.43 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)CCc1cc(OC)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)O)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a solution of ethyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methoxyphenyl)propanoate (450 mg) in methanol (4.0 mL) and THF (8.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (319 mg) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(OCC)(=O)C>[CH2:21]([O:20][C:18]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCC1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCCCC1CCO
Reaction time: 2 h

Procedure:
To a solution of 2-piperidin-2-yl-ethanol (2.04 g in 50 mL methylene chloride) at 0° C. was added 2.64 mL of triethylamine and 5 mg N,N-dimethylaminopyridine. To the stirred solution, 2.45 mL of benzyl chloroformate was added dropwise and the reaction allowed to proceed at room temperature. After 2 hours, the mixture was diluted with ethyl acetate and washed sequentially with 10% aqueous sodium bisulfate, water and brine. The organic portion was dried over magnesium sulfate and purified by flash chromatography on silica gel (hexane:ethyl acetate, 70:30) to give the title compound (2.05 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29]C)/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[OH:29])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Compound 1 (770 mg, 1.87 mmol) obtained in Reference Example 1 was dissolved in 15 ml of methylene chloride. To the solution was added 5.6 ml (5.6 mmol) of boron tribromide (1.0M methylene chloride solution) under ice cooling in argon atmosphere, and the mixture was stirred overnight at room temperature. Methanol was added thereto and the mixture was separated with chloroform-an aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to give 550 mg (yield 77%) of Compound 54 as a yellow solid, which was then triturated with ether to give a yellow powder.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.C(OCC)(=O)C.[N+:20]([C:23]1[C:24]([NH2:30])=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>>[Br:1][CH2:2][C:3]1[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])=[N:30][C:24]2[C:25](=[CH:26][CH:27]=[CH:28][C:23]=2[N+:20]([O-:22])=[O:21])[N:29]=1
Reactant: O=C(CBr)C(=O)c1ccccc1Cl
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2nc(CBr)c(-c3ccccc3Cl)nc12
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-1-(2-chlorophenyl)propane-1,2-dione (Prepared in Example 81, 4.2971 g, 16.4325 mmol) in ethyl acetate (109.55 mL, 16.433 mmol) was added 3-nitro-1,2-phenylenediamine (2.5165 g, 16.433 mmol) at room temperature and the resulting red mixture was stirred at room temperature. After 26 h of stirring at room temperature, the mixture was concentrated under reduced pressure to give 2-(bromomethyl)-3-(2-chlorophenyl)-5-nitroquinoxaline including its regioisomer as a red syrup: LC-MS (ESI) m/z 378.0 and 379.9 [M+H]+. The crude product as a red syrup was carried on crude without purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:43]1([CH2:47][C@H:48]([CH:51]2[CH2:53][CH2:52]2)[NH:49][CH3:50])[CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[N:43]1([CH2:47][C@@H:48]([N:49]([CH3:50])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=2)[CH:51]2[CH2:53][CH2:52]2)[CH2:46][CH2:45][CH2:44]1
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: CN[C@H](CN1CCC1)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCC2)C2CC2)ccc1F
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
To a mixture of 4-fluoro-3-methylbenzoic acid (330 mg, 2.14 mmol) and DIPEA (0.508 mL, 2.92 mmol) in DCM (3 mL) was TBTU (687 mg, 2.14 mmol) added. After 10 min was a solution of (S)-2-(azetidin-1-yl)-1-cyclopropyl-N-methylethanamine (Compound L1) (300 mg, 1.94 mmol) in DCM (3 mL) added. The resultant mixture was stirred at r.t for 6 h. The mixture was washed with NaHCO3 (8% aq., 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (353 mg, 63%). Mixture of rotamers: 1H NMR (600 MHz, CD3OD) δ 0.04-0.14, 0.31-0.40, 0.40-0.48, 0.48-0.57, 0.59-0.66, 0.67-0.75, 0.92-1.06, 2.01-2.07, 2.07-2.16, 2.29, 2.30, 2.56-2.65, 2.76-2.88, 2.90, 2.94-3.00, 3.02, 3.09-3.21, 3.26-3.37, 3.80-3.91, 7.04-7.14, 7.22-7.40. Total no of protons: 23. HRMS (M+H)+: calculated 291.1873. found 291.1865.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl[CH2:23][CH2:24][CH2:25][N:26]([CH3:31])[CH:27]1[CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:27]1([N:26]([CH3:31])[CH2:25][CH2:24][CH2:23][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3([CH2:8][NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:16][CH:17]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Reactant: CN(CCCCl)C1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCOc1ccc(C2(CNc3ccccn3)CCOCC2)cc1)C1CCC1
Yield: 29.6 %

Procedure:
4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (386 mg, 1.36 mmol), N-(3-chloropropyl)-N-methylcyclobutanamine (241 mg, 1.496 mmol) and potassium carbonate (280 mg, 2.03 mmol) were stirred in DMF (2 ml) at 45° C. for 24 hours until complete. Reaction was partitioned between ethyl acetate (40 ml) and saturated sodium bicarbonate solution (50 ml), then the organic layer washed with water (50 ml). Organic layer separated and dried over sodium sulphate, filtered and concentrated in vacuo. Crude product purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 90:10:1 by volume) to give the title compound (165 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 1.55-1.72 (m, 2H), 1.80-1.99 (m, 6H), 2.00-2.09 (m, 2H), 2.10-2.20 (m, 4H), 2.40 (t, 2H), 2.80 (quintet, 1H), 3.50 (d, 2H), 3.54-3.62 (m, 2H), 3.78-3.88 (m, 2H), 4.00 (m, 3H), 6.20 (d, 1H), 6.50 (t, 1H), 6.92 (d, 2H), 7.22 (d, 2H), 7.32 (t, 1H), 8.00 (d, 1H). LRMS APCI+ m/z 410 [MH]+. HRMS ESI+ m/z 410.2794[MH]+.