Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.C(Cl)(=O)C([Cl:15])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][Cl:15]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1ccc(Cl)nc1Cl
Yield: 113.1 %

Procedure:
A solution of 2,6-dichloronicotinic acid (3.84 g), oxalyl chloride (2.0 g), and 1 drop of dimethylformamide in dichloromethane (25 ml), was stirred at room temperature for 18 hours. The solution was concentrated in vacuo to give 3.50 g of 2,6-dichloronicotinyl chloride which was added portionwise in dichloromethane (25 ml) to an ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (2.15 g) and diisopropylethylamine (2.03 g) in dichloromethane (50 ml). The mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield 2.65 g of the title as a an amorphous solid. m.p. 115-130° C. MS, m/z: 358.1 (M+H)+.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:31][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield as a colorless syrup from 1-cyclohexyloxy-2,2,6,6,-tetramethyl-piperidin-4-one and dodecylamine according to the procedure of Example 11B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccccc1F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4F)cc23)CC1
Yield: 79.4 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 5.4 μL (0.0458 mMol) 2-fluorobenzoyl chloride, 12.2 mg (80%) of the title compound were recovered.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:36][CH2:35][CH2:34][CH2:33][O:32][CH3:31])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Reactant: COCCCN
Agent: Cl
Product: COCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 20.9 mg (0.23 mmol) of 3-methoxypropylamine are reacted together by general method E. 29.8 mg (44.5% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C@:2]1([CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:4][O:3]1.[Cl:23][C:24]1[NH:25][CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1.C(=O)([O-])O.[Na+].O>C(#N)C>[Cl:23][C:24]1[N:25]([CH2:4][C@@:2]([CH3:1])([OH:3])[CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1
Reactant: C[C@]1(CN2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C[C@](O)(CN1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 31.5 %

Procedure:
To a suspension of (S)-1-(2-methyloxiran-2-ylmethyl)-4-(4-trifluoromethoxyphenyl)piperazine (0.43 g, 1.37 mmol) and 2-chloro-4-nitro-1H-imidazole (0.22 g, 1.51 mmol) in acetonitrile (4 ml), sodium hydrogencarbonate (0.17 g, 2.06 mmol) was added followed by stirring under reflux for 9 hours. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol (0.20 g, yield 31%) as a light yellow oil.
Reaction SMILES: [F:1][C:2]([N:5]=[C:6]=[O:7])([F:4])[F:3].[CH3:8][C:9]1[CH:10]=[C:11]([NH:15][OH:16])[CH:12]=[CH:13][CH:14]=1>C(OCC)C>[F:1][C:2]([F:4])([F:3])[NH:5][C:6]([N:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=1)[OH:16])=[O:7]
Reactant: O=C=NC(F)(F)F
Reactant: Cc1cccc(NO)c1
Solvent: CCOCC
Product: Cc1cccc(N(O)C(=O)NC(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of trifluoromethyl isocyanate (11.1 grams; 0.1 mol) in diethyl ether (50 ml) is added dropwise, with stirring, to a solution of N-(3-methylphenyl) hydroxylamine (12.3 grams; 0.1 mol) in diethyl ether (50 ml) at room temperature. Stirring is continued for a period of about 1 hour resulting in the formation of a precipitate. The precipitate is recovered by filtration, is washed and dried to yield 1-trifluoromethyl-3-(3'-methylphenyl)-3-hydroxyurea.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([NH2:19])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.C([O-])(O)=O.[Na+].Cl[CH2:28][CH:29]=O.O>CCO>[F:21][C:2]([F:1])([F:20])[C:3]1[C:4]2[N:5]([CH:28]=[CH:29][N:19]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: O=CCCl
Reactant: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3nccn3c2)cc1
Yield: 69 %

Procedure:
To a mixture of 3-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine (12.77 g, 42 mmol) and NaHCO3 (5.96 g, 71 mmol) in EtOH (300 mL) was added chloracetaldehyde solution 55% in water (22 mL, 188 mmol), then refluxed overnight. The reaction mixture was concentrated and purified by column chromatography (CH2Cl2/Et2O 1:1) to give the product as a white crystalline solid (9.6 g, 69%). MS (ISP) 331.1 [(M+H)+].
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:16]1[CH2:22][CH2:21][CH2:20][C@H:17]1[CH:18]=[O:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:9]([N:16]1[CH2:22][CH2:21][CH2:20][C@H:17]1[C:18](=[O:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: Cl[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)c1ccccc1

Procedure:
10 ml (20 mmol) 2 M phenylmagnesium chloride (tetrahydrofuran) and 1.99 g (10 mmol) BOC-L-prolinal were allowed to react at −60–40° C. for 60 min according to procedure F. Yield of the crude product 3.06 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 2.18 g (7.6 mmol, 76%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 3.15 g. The product was purified with a silica column using 20–25% ethyl acetate in petroleum ether as eluent. Yield 1.65 g (6.0 mmol, 79%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH2:4][C:3]1=[O:15].O1CCCC1>CO>[OH:14][C@H:11]1[CH2:10][CH2:9][C@@H:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:15])[CH2:4]2)[CH2:13][CH2:12]1
Reactant: CN1CCN(C2CCC(=O)CC2)CC1=O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN([C@H]2CC[C@@H](O)CC2)CC1=O

Procedure:
17 ml of a 1M L-Selctride solution (in tetrahydrofuran) are added dropwise at −78° C. to 3.3 g 4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexan-1-one in 100 ml abs. tetrahydrofuran. After 5.5 hours 20 ml of methanol are added and the solution is evaporated down. The residue is purified by column chromatography. The mixture of cis- and trans-compound is separated by preparative HPLC.
Reaction SMILES: O[C@@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]2[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:3]1=2.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:39]([C@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]2[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:3]1=2)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N=[N+]=[N-]
Yield: 84.2 %

Procedure:
Heat a mixture of (R)-tert-butyl 5-hydroxy-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (1.60 g, 4.65 mmol), diphenylphosphoryl azide (DPPA, 1.4 mL, 6.50 mmol) and DBU (1.0 mL, 6.50 mmol) in toluene (20 mL) at 65° C. under nitrogen for 12 h. Add silica gel to the cooled mixture and remove the solvents under reduced pressure. Purify the residue by column chromatography, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless oil (1.45 g, 85%). APCI MS m/z 356 (M−N2)−.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([Br:9])[CH:6]=[CH:5][CH:4]=1.[CH2:10]([N:17]=[C:18]=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[Br:9][C:7]1[N:8]=[C:3]([N:2]([CH3:1])[C:18]([NH:17][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19])[CH:4]=[CH:5][CH:6]=1
Reactant: CNc1cccc(Br)n1
Reactant: CCCCCCCN=C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(Br)n1
Temperature: 100 °C
Yield: 71 %

Procedure:
2 g of 6-methylamino-2-brompyridine (prepared according to the procedure of Example 11, step a) are mixed with 3.0 mL of heptyl isocyanate. The mixture is heated for 12 hours at 100° C. The residue is chromatographed on silica gel (9/1 heptane/ethyl acetate). 2.45 g of 1-(6-bromopyrid-2-yl)-1-methyl-3-heptylurea are obtained. Yield=71%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29]([OH:31])=O)[CH2:12]1)(=[O:10])=[O:9].[CH2:32]([NH:36][C:37](=[O:44])[C:38](=[O:43])[C@@H:39]([NH2:42])[CH2:40][CH3:41])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([NH:36][C:37](=[O:44])[C:38](=[O:43])[C@@H:39]([NH:42][C:29]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:15][N:14]1[C:16]([C:18]1([C:21]2[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:17])=[O:31])[CH2:40][CH3:41])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCNC(=O)C(=O)[C@@H](N)CC
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Product: CCCCNC(=O)C(=O)[C@H](CC)NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-pentanoic acid butylamide in step 1. MS (m/e)=655.15 [M+H+].
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[CH2:34][CH2:35][NH2:36].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[CH2:34][CH2:35][NH:36][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: COc1ccc(OC)c(CCN)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2cc(OC)ccc2OC)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2,5-dimethoxy-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C25H33NO7 [M−H]−: 458.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([S:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:23][B-:24]([F:27])([F:26])[F:25].[H+]>C(OCC)C.C1C=CC=CC=1>[F:23][B-:24]([F:27])([F:26])[F:25].[C:3]1([S+:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of magnesium turning (12 g) in ethyl ether (500 ml), bromobenzene (83.5 g, 0.54 mole) was added dropwise under reflux with stirring and continued to stir for 1 hour under reflux. to this Grignard reagent, benzene (500 ml) was added and concentrated until 500 ml. To this resultant mixture, a solution of diphenylsulfoxide (30 g, 0.15 mole) in benzene (200 ml) was added and reacted with stirring for 40 hours under reflux. After the reaction mixture was cooled to 0° C., 40% tetrafluoroboric acid (50 ml) was added dropwise at 0°-5° C. and reacted with stirring for 5 hours at the same temperature. After standing at room temperature overnight, the aqueous layer separated was extracted with methylene chloride (100 ml×3), the organic layer was washed with H2O, dried over anhydrous sodium sulfate and dried. The residual crude solid was recrystallized from chloroform/ethyl ether to give 28 g of triphenylsulfonium tetrafluoroborate as white crystals. m.p. 291°-292° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[F:20])=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:17]2[CH:16]=[CH:15][C:14]([F:20])=[C:13]([CH:18]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]
Reactant: COC(=O)CCc1ccc(Oc2cc(Br)ccc2F)cc1C
Reactant: CCc1ccc(O)c(Oc2ccccc2)c1
Product: CCc1ccc(Oc2ccc(F)c(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(Oc2ccccc2)c1

Procedure:
The title compound is prepared according to Example 13, Step C by using 3-[4-(5-bromo-2-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester and 4-ethyl-2-phenoxy-phenol to afford 15 mg (11%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H27FO5 486, found 487 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:38]=[CH:39][CH:40]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]([O:22][CH:23]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:45]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:38]=[CH:39][CH:40]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]1[O:22][C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:45]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)C(OC(=O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C(c1cccc(OCc2ccccc2)c1)N1CCCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A mixture of 2-oxo-1,2-diphenylethyl 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylate (288 mg) and ammonium acetate (427 mg) in acetic acid (1.4 ml) was stirred under reflux for 3 hours, cooled to room temperature, and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with aqueous NaHCO3 (twice) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 1-(3-benzyloxybenzoyl)-2-(4,5-diphenyl-2-oxazolyl)piperidine (104 mg) as amorphous powder.
Reaction SMILES: C([Mg]Br)C.I[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1.[CH3:20][C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:24])[CH:22]=[O:23].[NH4+].[Cl-]>C1COCC1.O>[F:17][C:16]([F:19])([F:18])[C:8]1[CH:7]=[C:6]([CH:22]([OH:23])[C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:24])[CH3:20])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Reactant: CC(C)(C=O)NC(=O)OCc1ccccc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (1.63 mL, 1M in THF, 1.63 mmol) was added dropwise to a stirred solution of 1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 μL, 1.79 mmol) in dry THF (1 mL) at room temperature under N2 and the reaction was stirred for 30 min. The resulting solution was added to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (163.5 mg, 0.739 mmol) in dry THF (1 mL) at −20° C. and reaction was allowed to warm to room temperature over 3 h. Saturated NH4Cl (10 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=436.1; found=436.0 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H), 5.12-5.08 (m, 2H), 1.36 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.81 (s, 1H), 1.36 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18]>CCO>[CH2:16]([CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)C(=O)OCC
Yield: 87.6 %

Procedure:
To a solution of NaOEt prepared by dissolving 5.75 g (0.25 mol) of Na in 150 mL of absolute EtOH was added 39 mL (0.250 mol) of diethyl malonate with cooling in a water bath under N2. To the resulting solution was added 24 mL (0.250 mol) of isobutyl bromide. The mixture was refluxed under N2 for 14 hours. The ethanol was evaporated under reduced pressure and the residue was partitioned between CHCl3 and water. The aqueous Na2SO4 and evaporated. The residue was distilled under reduced pressure to give 47.2 g (0.219 mol, 88% of diethyl isobutylmalonate as a colorless liquid. Characteristic analytical data are as follows: bp 127°-135° C. (25 mm Hg); 1H NMR (300 MHz, CDCL3) δ4.20 (q, J=7 Hz, 4H), 3,41 (t, J=8 Hz, 1H), 1.80 (t, J=7 Hz, 2 H), 1.57 (m, 1H), 1.27 (t, J=8 Hz, 6H), 0.92 (d, J=7 Hz, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][S:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:23]=1[C:29]([F:32])([F:31])[F:30].CCO>CN(C=O)C.Cl>[Cl:21][C:22]1[C:23]([C:29]([F:30])([F:31])[F:32])=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:18][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][S:15][CH2:16][CH3:17]
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Reactant: CCSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCSC[C@H](Oc1cccc(Cl)c1C(F)(F)F)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethylsulfanyl-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 mg, 40 μmol) was dissolved in DMF (174 μL). NaH (1.3 mg, 54.5 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorobenzotrifluoride (21.6 mg, 109 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (890 μL, 1.1 mmol) and stirred overnight at room temperature. The product was concentrated and the crude product was dissolved in 1:1 AcOH/H2O (1.5 mL) then purified by preparative HPLC to yield the title compound as a mono-TFA salt (3.4 mg, purity 97%). MS m/z: [M+H]+ calcd for C15H19ClF3NOS, 354.08. found 354.0.
Reaction SMILES: S(O[CH2:12][CH2:13][N:14]1[C:18]2=[CH:19][C:20]3[N:21]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=4)[CH:23]=[N:24][C:25]=3[CH:26]=[C:17]2[CH:16]=[N:15]1)(C1C=CC(C)=CC=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CN(C=O)C>O>[N:36]1([CH2:12][CH2:13][N:14]2[C:18]3=[CH:19][C:20]4[N:21]=[C:22]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=5)[CH:23]=[N:24][C:25]=4[CH:26]=[C:17]3[CH:16]=[N:15]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1ccc(-c2cnc3cc4cnn(CCOS(=O)(=O)c5ccc(C)cc5)c4cc3n2)cc1F
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cnc3cc4cnn(CCN5CCCCC5)c4cc3n2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A mixture of 1-(2-tosyloxyethyl)-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (0.3 g), piperdine (0.11 g) and 20 ml of anhydrous DMF is stirred at room temperature overnight. The mixture is heated to gentle reflux for 21/2 hours. After cooling, it is poured into water and the precipitate is filtered, washed with water and air dried. This is then purified by chromatography using (3:7-1:9) methylene chloride in ethylacetate as eluent. 0.220 g of desired product to obtain 1-(2-piperdin-1-ylethyl)-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 117°-120° C. (dec)).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12](O)=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5].CN(C)C=O.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12]([Cl:30])=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reaction time: 2 h

Procedure:
3.37 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid are suspended in 100 ml of toluene; 0.1 ml of dimethylformamide and 1.64 g of thionyl chloride are added and the whole is heated to 80°, stirred for 2 hours at 80°-90° and concentrated to dryness by evaporation under reduced pressure. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid chloride is obtained which can be used without being further treated.