Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([NH2:10])[CH:9]=1)([CH3:3])[CH3:2].[S-:14][C:15]#[N:16].[Na+].[Br-].[Na+].BrBr>CO>[CH:1]([C:4]1[C:5]([S:14][C:15]#[N:16])=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([NH2:10])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc([N+](=O)[O-])c(N)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(N)c([N+](=O)[O-])cc1SC#N

Procedure:
The title compound was prepared according to General Method 13 using 5-isopropyl-2-nitro-phenylamine (prepared in Example PP-1; 5.4 g, 30 mmol), sodium thiocyanate (14.6 g, 180 mmol), sodium bromide (3.7 g, 35.99 mmol), bromine (5.75 g, 36.0 mmol), and MeOH (100 mL). The crude reaction mixture was purified by flash silica gel chromatography (5%-50% EtOAc in hexanes as eluents). MS(APCI): 238 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCC(=O)OC)ccc(C(C)=O)c1O
Yield: 66.7 %

Procedure:
A mixture of 2.92 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.91 g of methyl 5-bromopentanoate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 16 hours. The usual workup followed by chromatography on 350 g of silica gel and elution with 5% ethyl acetate-toluene gave 3.07 g (66% yield) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy) pentanoic acid methyl ester, the titled compound, as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][N:12]([C:20](Cl)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1.[CH3:32][S:33]([CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:35])=[O:34]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:13][N:12]([C:20]([N:42]4[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][CH2:36][S:33]([CH3:32])(=[O:34])=[O:35])[CH2:44][CH2:43]4)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)N2CCN(CCCS(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 9, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride prepared in Example 8 (53 mg, 0.11 mmol) was reacted with 1-(3-methanesulfonyl-propyl)-piperazine (34 mg, 0.14 mmol) and triethylamine to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1′-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (Yield, 61 mg, 79%).
Reaction SMILES: [CH2:1]([N:11]([CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:23][CH2:24][CH2:25][CH2:26][Cl:27].CO>CCCCCC>[Br-:23].[Cl:27][CH2:26][CH2:25][CH2:24][N+:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:22]
Reactant: CCCCCCCCCCN(C)CCCCCCCCCC
Reactant: ClCCCBr
Solvent: CCCCCC
Solvent: CO
Product: CCCCCCCCCC[N+](C)(CCCCl)CCCCCCCCCC
Product: [Br-]
Temperature: 65 °C

Procedure:
A two-liter, 3-necked, round-bottomed flask equipped with air condensers and a magnetic stirring plate was charged with N,N-didecylmethylamine (65.49 grams, 0.21 moles), 1-bromo-3-chloropropane (33.06 grams, 0.21 moles) and methanol (250 mL). Reaction was maintained at 65° C. for six days. Methanol was removed by rotary evaporation under reduced pressure to yield an oil. To the oil was added hexane (200 mL) causing a white solid to slowly form. The solvent was decanted off from the mixture. The remaining solid dried overnight under vacuum. Yield 81.67 grams 0.17 moles, 82%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14](Cl)[CH3:15].[OH-].[Na+].C(N(CCCC)CCCC)CCC>ClC1C=CC=CC=1Cl>[CH2:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:15]
Reactant: CCCl
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: CCCCN(CCCC)CCCC
Product: CCn1c2ccccc2c2ccccc21
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A 0.5-liter autoclave equipped with a stirrer was charged with carbazole (82.4 g), o-dichlorobenzene (100 g), ethyl chloride (40.2 g), 48% sodium hydroxide (55.8 g) and tributylamine (9.2 g). After the atmosphere in the autoclave was replaced with nitrogen gas, the autoclave was heated to the reaction temperature of 100° C. and the reaction mixture was stirred at the same temperature for 9 hours, while keeping the temperature. After completion of the reaction, the mixture was cooled to 50° C. The same procedures as those described in Example 1 gave 275.9 g of an o-dichlorobenzene solution of N-ethylcarbazole. The analysis of this solution by chromatography revealed that the content of N-ethylcarbazole was 32.9% and the yield thereof was 94.3%.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=1.Cl[C:24]1[N:29]2[CH:30]=[CH:31][N:32]=[C:28]2[CH:27]=[C:26]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])[N:25]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:40][C:34]1[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=1[C:26]1[N:25]=[C:24]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)[N:29]2[CH:30]=[CH:31][N:32]=[C:28]2[CH:27]=1
Reactant: NCCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)ccc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
104 mg (0.32 mmol) of the amine (Example 57A) are introduced into 3 ml of isopropanol, 73.6 mg (0.25 mmol) of 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine and 95.6 mg (0.74 mmol) of DIPEA are added, and the mixture is heated in a microwave at 150° C. for 2 h. Purification by preparative HPLC results in 96 mg (82% of theory) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[CH:14]=3)[C:9]2=[O:23])=[CH:5][CH:4]=1.C(O)C.[BH4-].[Na+]>C1COCC1>[OH:20][CH2:19][C:18]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:23])[N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=1)[CH2:17][CH2:16]2)([CH3:21])[CH3:22]
Reactant: COc1ccc(CN2CCc3cc(C(C)(C)C=O)ccc3C2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3cc(C(C)(C)CO)ccc3C2=O)cc1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
180 mg 2-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionaldehyde (0.54 mmol, 1 eq) was cooled to zero° C. in 20 ml of a 1:1 mixture of ethanol and THF. 20 mg sodium borohydride (0.54 mmol, 1 eq) was added and the mixture was stirred at 0°° C. for 1 hour. Quenched with water, then 2 drops glacial acetic acid, stirred for 5 minutes, and the mixture concentrated under vacuum to remove the majority of solvents, added saturated bicarb solution, extracted ethyl acetate 2×, dried ethyl acetate over MgSO4, and concentrated to give 180 mg 6-(2-Hydroxy-1,1-dimethyl-ethyl)-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one (M+H=340) which was used directly in the next reaction with no purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][CH:32]([F:44])[O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[F:44][CH:32]([F:31])[O:33][C:34]1[CH:35]=[C:36]([S:40]([N:19]2[CH2:18][CH:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]2=[O:28])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(OC(F)F)c4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3-(difluoromethoxy)benzenesulfonyl chloride to give the title compound as a colorless solid. MS: 584.7 ([M]+)
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.[CH3:13][C:14]1[N:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([C:25]#[N:26])[C:18](=[O:24])[NH:19]2>O>[CH3:13][C:14]1[N:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([C:25](=[N:2][OH:3])[NH2:26])[C:18](=[O:24])[NH:19]2
Reactant: Cc1nccc2[nH]c(=O)c(C#N)cc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nccc2[nH]c(=O)c(C(N)=NO)cc12
Yield: 96.3 %

Procedure:
To a solution of hydroxylamine hydrochloride (4.17 g) in water (50 ml) was added sodium carbonate (3.18 g) with stirring under ice cooling. To the solution were subsequently added ethanol (200 ml) and 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile (3.70 g), and the mixture was refluxed for 2 hours. After distilling off the solvent under reduced pressure, water was added to the residue, and the precipitated crystals were separated by filtration. The product was washed with water, isopropanol, diisopropyl ether in this order, and dried to give 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridin-3-amidoxime (4.2 g). This compound was used in the next reaction without being purified.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8].[OH-:23].[Na+].[CH2:25](O)[CH3:26]>O>[OH:23][CH:2]([CH2:22][O:1][CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:8])=[O:9]
Reactant: CCO
Reactant: [OH-]
Reactant: CCOC(=O)CCCCCCN(CCCC1CO1)S(C)(=O)=O
Agent: [Na+]
Solvent: O
Product: CCOCC(O)CCCN(CCCCCCC(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 7-[N-(4,5-epoxypentyl)-methanesulfonamido]heptanoate (7.0 g., 0.02 mole) in ethanol (150 ml.) is added sodium hydroxide (1.84 g., 0.046 mole) dissolved in water (15 ml.). This solution is stirred at room temperature for 18 hours, then concentrated to one-half volume under reduced pressure. Water (150 ml.) is added and this aqueous solution is extracted with ether (2 × 100 ml.). The aqueous layer is then acidified (dilute hydrochloric acid) and extracted with ethyl acetate (2 × 150 ml.). The organic phase is washed with brine, dried over sodium sulfate, then evaporated in vacuo. The yield of subject compound is 4.0 g. (54%) of pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].C[O-].[Na+].Cl>CN(C=O)C.O.CO>[C:12]([C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)([OH:14])=[O:13]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=C1OCc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Temperature: 130 °C
Reaction time: 6.5 h
Yield: 82.8 %

Procedure:
A solution of 4-hydroxyphenylacetic acid (90.0 g, 0.58 mol; assay >98%) and phthalide (85.07 g, 0.63 mol) in DMF (323 g) was heated to an internal temperature of 130° C. The pressure was reduced to 800 mbar and sodium methoxide (224.6 g, 1.25 mol, assay: 30% methanolic solution) was added slowly to the mixture maintaining the internal temperature above 100° C. During the addition methanol was distilled off, and after the addition the distillation was continued under normal pressure until the internal temperature increased to 130° C. again (260 g distillate). After stirring at this temperature for 6.5 h, phthalide (8.5 g, 0.06 mol) was added and the mixture was stirred overnight (16 h). Afterwards the mixture was cooled to 100° C. and hydrolyzed with water (1040 g). After cooling to <10° C., the pH of the mixture was adjusted to pH 1 with hydrochloric acid (163.5 g, 1.43 mol; assay: 32%). The product was filtered off, washed with water (700 g) and dried under vacuum for 15 hours at 60° C. to give crude 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (yield: 174.6 g, 0.48 mol, 82.1%; HPLC assay: 78.0%).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(O)=O.[OH:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][CH:16]=1.[S:26]([NH:36][C@H:37]([C:39](Cl)=[O:40])[CH3:38])([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>O1CCCC1>[S:26]([NH:36][C@H:37]([C:39]([O:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][CH:16]=1)=[O:40])[CH3:38])([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=1)(=[O:27])=[O:28]
Reactant: Oc1c[nH]c(-c2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Oc2c[nH]c(-c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of anhydrous tetrahydrofuran (THF, 450 mL), pyridine (43.8 mL; 0.542 mol; 1.2 eq) and trifluoroacetic acid (85.0 mL; 1.10 mol; 2.4 eq), maintained at 0° C. under an inert gas atmosphere, was treated in one portion with 3-hydroxy-5-phenylpyrrole (3) (71.5 g; 0.45 mol; 1.0 eq) followed immediately by the dropwise addition, over 5-10 minutes of a solution of freshly prepared N-tosyl-L-alaninyl chloride (141.0 g; 0.54 mol; 1.2 eq) in anhydrous THF (450 mL). The resulting mixture was stirred for 15 minutes at 0° C. The reaction was then quenched by addition of a solution of 1.0M aqueous citric acid (315 mL) and EtOAc (1.35 L). After brief mixing the phases were separated and the organic layer washed with a solution of aqueous NaCl (360 mL; 0.18 g NaCl per mL of water). The organic layer was next extracted twice with a solution of 5% aqueous NaHCO3 (1.35 L each), and then washed with another portion of aqueous NaCl (360 mL; 0.18 g NaCl per mL of water). The reddish brown organic layer was stirred at ambient temperature for 15 minutes with MgSO4 (101 g) and Darco-G60 (143 g), then filtered through Celite and evaporated to dryness under vacuum from a 37° C. bath to give (4) as a pinkish-white solid. The crude product was ground to a powder and dissolved in warm (50° C.) THF (250 mL), stirred vigorously and diluted with n-hexane (250 mL). The stirring was continued for 1 hour at ambient temperature as the product crystallized. The solid was filtered, washed with toluene (about 1 L) until the filtrate was colorless, then dried overnight to yield the title compound (112 g; 65%) as a white powder with mp=154.5°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][OH:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:33][CH2:34][OH:35])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[CH:30][CH:31]=1
Reactant: OCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCO)c(=O)c2c1nc(Oc1cccc(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Yield: 28.9 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (60 mg, 0.133 mmol, example 1) in DMF (1 mL) was added 2-bromoethanol (16.5 mg, 0.133 mmol) and cesium carbonate (86.6 mg, 0.266 mmol). The resulting mixture was subjected to microwave irradiation at 120 for 20 min in a sealed tube. The mixture was diluted with ethyl acetate (5 mL) and extracted with saturated aqueous ammonium chloride solution. The organic phase was dried and concentrated to give crude product which was purified preparative HPLC to give 7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (19 mg, 28.8% yield) as white solid.
Reaction SMILES: [Cl:1][CH:2]([F:9])[C:3]([F:8])([F:7])[C:4](Cl)=[O:5].[CH2:10]([O:12][C:13](=[O:35])[CH:14]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:11]>ClCCl.N1C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:35])[CH:14]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:4](=[O:5])[C:3]([F:8])([F:7])[CH:2]([Cl:1])[F:9])[CH:29]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:11]
Reactant: O=C(Cl)C(F)(F)C(F)Cl
Reactant: CCCCCCCCCCCCC(Oc1cccc(N)c1)C(=O)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)OCC

Procedure:
An amount of 63.35 g (0.35 mol) of 3-chloro-2,2,3-trifluoro-propionyl chloride is added dropwise in 30 min to a solution of 109 g (0.3 mol) of 2-(m-aminophenoxy)-myristic acid ethyl ester in 450 ml of dichloromethane and 48 ml of pyridine. A slight reflux is observed. The mixture is then refluxed for 2 h. Subsequently, the reaction mixture is washed first with 1N hydrochloric acid and next with water until neutral. The solvent is removed by evaporation.
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[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl[CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:30][CH2:31][CH2:32][C:33]2=[O:34])=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCCCl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N2CCCC2=O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (1.0 g, 3.5 mmol) in THF (15 ml) was added triethylamine (0.59 mL, 4.3 mmol). The mixture was cooled in an ice bath and a solution of 4-chlorobutyryl chloride (0.48 mL, 4.3 mmol) in THF (5 mL) was added dropwise. After stirring for 1 h at room temperature the precipitate was filtered and the organic phase was evaporated. The residue was dissolved in methanol (20 mL), sodium bicarbonate (1 spatula) was added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was extracted (dichloromethane/water). Then the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane/ethyl acetate=100:0 to 60:40) afforded the title compound (250 mg, 20%) (as the most polar component of two formed in the reaction) which was obtained as a white solid. MS: m/e=351.4 [M+H]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C@:11]12[CH2:35][CH2:34][C@@:33]([C:37]([F:40])([F:39])[F:38])([OH:36])[CH2:32][C@H:12]1[CH2:13][CH2:14][CH2:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]>CN(C=O)C>[Br:8][C:24]1[C:23]2[N:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:21]=[CH:20][C:19]=2[CH:18]=[C:17]2[C@@:11]3([CH2:9][CH3:10])[CH2:35][CH2:34][C@@:33]([C:37]([F:40])([F:39])[F:38])([OH:36])[CH2:32][C@H:12]3[CH2:13][CH2:14][CH2:15][C:16]=12
Reactant: CC[C@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC[C@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Temperature: 25 °C
Yield: 49 %

Procedure:
NBS (0.011 g, 0.064 mmol) was added to a solution of (3R,4aR,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (15, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.022 g, 0.049 mmol) in DMF (0.5 mL) and the mixture was heated to about 60° C. for about 3 h. After cooling to rt, the reaction was quenched with ice (5 g). Sat. Aq. Na2CO3 (10 mL) and EtOAc (20 mL) were added. The layers were separated and the organic layer was washed with water (10 mL) then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-27% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure. The residue was lyophilized to yield (3R,4aR,12bS)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (46, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.013 g, 49% yield); LC/MS, method 2, Rt=3.13 min.; MS m/z: 525 and 527 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 7.90 (s, 1H), 7.57-7.50 (m, 2H), 7.38-7.30 (m, 2H), 5.56 (s, 1H), 3.56-3.44 (m, 1H), 3.03-2.88 (m, 1H), 2.43-2.18 (m, 2H), 2.16-1.66 (m, 7H), 1.64-1.38 (m, 4H), 0.68 (t, J=7.3 Hz, 3H).