Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]([F:45])([F:44])[C:27]1[CH:43]=[CH:42][C:30]([CH:31]=[N:32][N:33]2[CH2:38][CH2:37][N:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:45][C:26]([F:25])([F:44])[C:27]1[CH:43]=[CH:42][C:30]([CH:31]=[N:32][N:33]2[CH2:34][CH2:35][N:36]([C:39]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:40])[CH2:37][CH2:38]2)=[CH:29][CH:28]=1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C(Cl)N1CCN(N=Cc2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@](O)(COC(=O)N1CCN(N=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (2.75 g, 11.66 mmol), N,N-diisopropylethylamine (2.71 ml, 15.54 mmol) and 4-dimethylaminopyridine (0.19 g, 1.55 mmol) were added to a suspension of 4-(4-trifluoromethylbenzylideneamino)piperazine-1-carbonylchloride (2.48 g, 7.77 mmol) in toluene (40 ml) followed by stirring at 100° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylbenzylideneamino)piperazine-1-carboxylate (4.03 g, quantitative) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C:19]([CH2:25][C:26]4[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=4)[O:29][CH2:30][C:31]([O:33]CC)=[O:32])([OH:24])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:40]>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C:19]([CH2:25][C:26]4[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=4)[O:29][CH2:30][C:31]([O-:33])=[O:32])([OH:24])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:40]
Reactant: CCOC(=O)COc1cccc(CC2(O)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])COc1cccc(CC2(O)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 6 h

Procedure:
To a solution of ethyl {3-{[2-(4,5-diphenyloxazole-2-yl)-1-hydroxy-2-cyclohexen-1-yl]methyl}phenoxy}acetate (60 mg) in ethanol (5 ml) was added 1N-NaOH solution (0.12 ml) at room temperature. After being stirred for 6 hours, the mixture was evaporated. The residue was added with diethyl ether. The resulting solid was collected by filtration to give sodium {3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-cyclohexen-1-yl]methyl}phenoxy}acetate (34 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=1>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1cccnc1Br
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ncccc2F)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of methyl 2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.95 mol) in THF (4 L), was added portionwise a solution of potassium carbonate (807 g, 5.85 mol) in water (1.6 L), followed by 2-bromo-3-fluoropyridine (361 g, 2.05 mol) and the mixture degassed with argon. To this mixture was added tetrakis(triphenylphosphine)palladium (56.4 g, 48.8 mmol) and the mixture heated at reflux for 5 h. The mixture was cooled to room temperature and the organic layer separated and washed with brine (1 L). This organic solution containing the title compound was used directly in the next reaction (Preparation 27A).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2cccc(C(F)(F)F)c2)nc2ncnn12
Product: FC(F)(F)c1cccc(-c2cc(Cl)n3ncnc3n2)c1

Procedure:
A mixture of 3.50 g. of 7-hydroxy-5-(m-trifluoromethylphenyl)-1,2,4-triazolo[1,5-a]pyrimidine and 25 ml. of phosphorus oxychloride is refluxed for 6 hours. The excess reagent is removed by evaporation; ice is added and 1 N sodium hydroxide is added until the aqueous phase is basic to indicator paper. The compound is extracted with methylene chloride and the solution passed through a short column of a hydrous magnesium silicate. Evaporation of eluent gives the desired compound as a light yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[O:5][CH2:6][CH2:7][N:8]=1.BrCCC(O)=[O:13].C1N=CN(C(N2C=NC=C2)=O)C=1.C(CN)O>>[OH:5][CH2:6][CH2:7][NH:8][C:4](=[O:13])[CH2:3][CH2:2][Br:1]
Reactant: O=C(O)CCBr
Reactant: BrCCC1=NCCO1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: NCCO
Product: O=C(CCBr)NCCO

Procedure:
The required intermediate, 2-(2-bromoethyl)oxazoline, is prepared in a two-step process starting with 3-bromopropionic acid. Reaction of this acid with CDI followed by ethanolamine gives N-(2-hydroxyethyl)-3-bromopropionamide. Treatment of this compound with triphenylphosphine (PPh3) and DEAD in THF yields 2-(2-bromoethyl)oxazoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19].Cl>C(=S)=S>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([C:18](=[O:20])[CH3:19])=[CH:12][CH:13]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 200 g. of 2-fluorobiphenyl in 1500 ml. of CS2 was cooled to 0°-5° C. and treated with 200 g. of aluminum chloride over 140 minutes and then with 113 g. of acetyl chloride over 165 minutes. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured carefully into ice and hydrochloric acid, and organic material was extracted with a mixture of diethyl ether and ethyl acetate. The organic extract was washed with water, 10% sodium hydroxide, and water, and dried over sodium sulfate. Evaporation of the solvents in vacuo and recrystallization of the solid residue from hexane gave (4'-(2-fluorophenyl)acetophenone. This was recrystallized from hexane to give two crops.
Reaction SMILES: [F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:23])([F:1])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=2)[N:12]=1
Reactant: COc1ccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 115 °C
Yield: 98.1 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazolin-4(3H)-one (480 mg, 1.5 mmol) were added DIEA (0.55 mL, 3.0 mmol) and phosphorous oxychloride (10 mL, 108 mmol), and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. Toluene was added and evaporated twice to remove residual phosphorous oxychloride. The residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL), and the separated EtOAc layer was diluted with EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL) and brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazoline as a brown viscous oil (500 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: BrCCCc1ccccc1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Product: Cc1cc(CCCCc2ccccc2)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 53, Step B, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with 1-bromo-3-phenylpropane to give 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(4-phenylbutyl)pyridine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7].[CH3:42][CH2:43][CH:44]([NH2:47])[CH2:45][CH3:46].C(N(C(C)C)C(C)C)C.CN(C=O)C>O.C(OCC)(=O)C>[CH3:42][CH2:43][CH:44]([NH:47][CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7])[CH2:45][CH3:46]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCl)c4)sc4c3CCCC4)cc2)cc1
Reactant: CCC(N)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)NCc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
A mixture of 8.00 g of methyl 4-[2-(4-{[(2-{[3-(chloromethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 4.8 mL of pentan-3-amine, 3.5 mL of N-ethyl-N-isopropylpropan-2-amine, and 80 mL of DMF was stirred for 13 hours at 80° C. Ethyl acetate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (2% methanol/chloroform), thereby obtaining 6.57 g of methyl 4-{2-[4-({[2-({3-[(pentan-3-ylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][NH:10][CH:11]([CH2:13][CH3:14])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:8][C:4]1[N:3]=[C:2]([N:10]([CH3:9])[CH:11]([CH3:12])[CH2:13][CH3:14])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CCC(C)NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(C)N(C)c1cncc(Cl)n1
Temperature: 80 °C
Reaction time: 40 h
Yield: 72 %

Procedure:
A mixture of 2,6-dichloropyrazine (1.49 g), N-methylbutan-2-amine (1.31 mL), potassium carbonate (2.07 g) and DMA (10 mL) was stirred at 80° C. for 40 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (1.43 g, 72%) as a pale-yellow oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C:28](=[O:31])[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[Si:1]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C@H:28]([OH:31])[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H]1CC[C@H]2C(C)(C)C(=O)CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H]1CC[C@H]2C(C)(C)[C@H](O)CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a solution of the above Compound (12b) (175 mg, 0.35 mmol) in 2 ml of methanol was added 17 mg (0.45 mmol) of sodium borohydride under ice-cooling, and the mixture stirred for 30 min. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; chloroform:methanol=50:1) to give 106 mg (60%) of Compound (36).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([NH2:37])[CH2:35][NH2:36].C1C(=O)N(Br)C(=O)C1>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[NH:36][CH2:35][CH2:34][N:37]=3)[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:32])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C=O)cc2n1Cc1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C3=NCCN3)cc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-formyl-2-isopropyl-1H-indole-3-carboxamide (Compound 53, 18 mg, 0.040 mmol) in CH2Cl2 (1 ml) at 0° C. under argon was added ethylene diamine (2.5 mg, 0.042 mmol). The mixture was stirred at 0° C. for 30 minutes, and then added NBS (8 mg, 0.042 mmol). The reaction was stirred at 25° C. for 12 h, quenched with NaHCO3 (aqueous), diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (100% EtOAc) to yield the title compound as a light yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:13])[C@H:4]1[C:8]([CH3:10])([CH3:9])[O:7][C:6]([CH3:12])([CH3:11])[O:5]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>CCOCC>[CH3:11][C:6]1([CH3:12])[O:5][C@@H:4]([C:3]([Cl:13])=[N:2][O:1][S:15]([CH3:14])(=[O:17])=[O:16])[C:8]([CH3:9])([CH3:10])[O:7]1
Reactant: CC1(C)O[C@@H](C(Cl)=NO)C(C)(C)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H](C(Cl)=NOS(C)(=O)=O)C(C)(C)O1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
(R)-N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride (12.4 g, 59.7 mmol) was dissolved in Et2O (200 mL) and cooled in an ice bath. Methanesulfonyl chloride (4.6 g, 59.7 mmol) was added. Triethylamine (8.3 ml, 59.7 mmol) was added slowly and the reaction was stirred in an ice bath for 30 minutes. The reaction was filtered and concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (11.3 g, 39.55 mmol, 66.22% yield) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:16][CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:19]1([S:25][CH2:26][CH2:27]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[ClH:29]>O.CN(C)C=O>[ClH:29].[C:19]1([S:25][CH2:26][CH2:27][N:16]2[C:9]3=[N:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1cc(-c2ccncc2)nc2n1CCN2
Reactant: BrCCSc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccncc2)nc2n1CCN2CCSc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.2 g (0.93 mmol) of 7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in ml of anhydrous N,N-dimethylformamide was added 48.5 mg (1.21 mmol) of sodium hydride (60% suspension in mineral oil) and the resulting mixture was heated at 70° C. during 30 min. There was added 0.32 g (1.49 mmol) of 2-bromoethyl phenyl sulfide and heating was continued at 130° C. during 1 h. Water was added to the cooled mixture and the resulting solution extracted with ethyl acetate. The combined extracts were washed with water and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/diethylamine in the proportions 98/2/0.2 to obtain pure compound as free base. The compound was converted to the hydrochloride salt by addition of hydrochloric acid to an isopropylic solution of the free base. There is obtained 0.11 g of product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[C:4]([F:17])[CH:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:23]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][C:24]=5[N:25]([CH3:28])[C:26]=4[CH:27]=3)[C:10](=[O:14])[CH:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5F)cc4=O)cc31)CCNCC2
Temperature: 135 °C
Reaction time: 22 h
Yield: 57.8 %

Procedure:
A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (87 mg, 0.34 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (143 mg, 0.380 mmol), CuI (78 mg, 0.41 mmol), 8-hydroxyquinoline (10 mg, 0.068 mmol) and Cs2CO3 (124 mg, 0.38 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 22 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded an off-white powder. 2 N HCl in Et2O (100 mL) was added to a solution of the yellow residue in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 22 h. The suspension was filtered, and the solid was washed with Et2O and put in a vacuum oven at 40° C. for 2 h to afford 48 mg (29%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 9.21 (br s, 2H), 7.63 (dd, J=8.0, 8.0 Hz, 1H), 7.57-7.50 (m, 3H), 7.43 (d, J=1.5 Hz, 1H), 7.39 (dd, J=8.5, 2.0 Hz, 1H), 6.95 (dd, J=8.5, 2.0 Hz, 1H), 6.08 (dd, J=7.5, 3.0 Hz, 1H), 6.02 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 3.69 (s, 3H), 3.41-3.31 (m, 4H), 3.28-3.22 (m, 2H), 3.16-3.09 (m, 2H); ESI MS m/z 452 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH:27]1(N=C=NC2CCCCC2)CCCC[CH2:28]1>CCO.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([O:25][CH2:27][CH3:28])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C/C(=C\c1ccc(C(=O)O)s1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)s1

Procedure:
A suspension of 0.161 g (0.437 mmol) of 5-((E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl)-2-thiophenecarboxylic acid, (Compound 21, 0.03 g, 0.655 mmol) in EtOH, 0.099 g (0.48 mmol) of 1,3-dicyclohexylcarbodiimide, and 5.3 mg (0.044 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate washed with water and brine. The organic layers were combined and dried (MgSO4), The solvent was removed in-vacuo and the residue purified using flash chromatography (SiO2, 5% ethyl acetate in hexanes) to give the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[CH3:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Reaction time: 3 h

Procedure:
To a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C, 12.31 g, 36.2 mmol) in abs ethanol (160 ml) was added 1N NaOH (50 ml) at room temperature. The reaction mixture was stirred for 3 hours and then acidified with 1M HCl. The occuring white precipitate was filtered, washed with water and dried under vacuum to provide the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][CH:3]=1.Br>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
(2R,4S)-Methyl 2-(4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.86 g, 2.68 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 15.52 mL, 88.60 mmol) and the solution stirred at room temperature overnight. The solvent was evaporated and the residue was purified by preparative HPLC (Instrument: Agilent, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) and on a XBridge C18 column (10 μm 250×19 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 19 mL/min. 5-((2R,4S)-2-(4-Fluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (167 mg, 23%) was isolated. 1H NMR (400 MHz, dmso) δ 1.27-1.53 (m, 2H), 1.81-1.98 (m, 2H), 2.67-2.77 (m, 1H), 2.78-2.91 (m, 1H), 3.10 (d, 1H), 3.63 (d, 1H), 5.67-5.77 (m, 1H), 7.04-7.16 (m, 2H), 7.34-7.45 (m, 2H). HRMS Calculated for [C14H15FN2O2+H]+: 263.1196. Found: 263.1201