Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.Cl.[NH2:5][C@@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>[Cl-].[Na+].O>[CH2:17]([O:16][C:14](=[O:15])[NH:5][C@@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (dispersion 55%) 0.33 g (7.5 mmol) is washed with petrolether and the solvent is removed by separation (decantation). Then, the sodium hydride is carefully suspended in dimethylformamide (12.5 ml). To this suspension (R)-(+)-3-aminoquinuclidine dihydrochloride 0.50 g (2.5 mmol) is added. The initially exothermic reaction is then stirred at room temperature for one hour and then carbobenzoxy chloride 0.39 ml (2.75 mmol) is added to the reaction mixture within 15 minutes. The again initially exothermic reaction is stirred at room temperature for 90 minutes, then the mixture is poured into 10% brine (NaCl/water solution) and then four-times extracted with toluene. The combined organic phases are dried and evaporated. The crude oily residue is dissolved in dioxane (5 ml) and 0.31 ml of a 4 M hydrochloric acid is added. The mixture is then stirred at room temperature till the product precipitates. The crystals are filtered, washed with dioxane and ether and dried to give the title product. Mp=228-229° C. Optical rotation +6.3° (c=0.5, water).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[C:19]([NH:26][CH2:27][CH2:28][NH2:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:29][CH2:28][CH2:27][NH:26][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1cnc([N+](=O)[O-])c(-c2ccc(Cl)cc2Cl)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (1.4 g, 4.0 mmol) in DMF (10 ml) were added Boc-ethylenediamine (960 mg, 6.0 mmol) and DIPEA (1.5 ml). The solution was stirred overnight at 80° C. The solution was cooled to room temperature, taken in ethyl acetate and water. The layers were separated and the organic layer was washed with water and brine, dried, concentrated and purified to afford the title product.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])(=[O:5])=[O:4].[CH:25]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]O)[CH:36]=2)[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1.O>[CH:25]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][O:13][C:11]3[CH:10]=[CH:9][C:8]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[F:22])=[C:7]([O:6][S:3]([C:2]([F:23])([F:1])[F:24])(=[O:5])=[O:4])[CH:12]=3)[CH:36]=2)[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][CH2:26]1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2OS(=O)(=O)C(F)(F)F)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OS(=O)(=O)C(F)(F)F)c2)c1)C1CC1
Yield: 80.8 %

Procedure:
To a solution of 2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl trifluoromethanesulfonate (1.30 g) in THF (30 mL) were added ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (1.02 g), triphenylphosphine (1.87 g) and a 40% solution of diethyl azodicarboxylate in toluene (3.2 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].C(O)(=O)C.Br(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2nc(C)sc2C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [O-][Br+2]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(O)cc2)c(C(C)C)s1
Reaction time: 18 h
Yield: 84.1 %

Procedure:
While 35.8 g of 5-isopropyl-4-(4-methoxy-phenyl)-2-methyl-1,3-thiazol (5) prepared in Example 3 were added to 86 ml of acetic acid and stirred, 500 ml of 48% bromic acid were added. Subsequently, the temperature was gradually increased and stirring under reflux was continued for 18 hr. The temperature was decreased to room temperature, and 400 ml of dichloromethane were added and stirring was further continued for 30 min. Then, the dichloromethane layer was removed. Thereafter, the obtained reaction solution was added with a saturated aqueous solution of potassium carbonate to be neutralized at pH 7-8, after which the precipitated solid was filtered and then washed with water, thus obtaining 28.4 g (yield: 84%) of a title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N+:13]([O-:25])=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3cnccc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: [O-][n+]1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine (0.920 g, 4.31 mmol) in dichloromethane (50 mL) was added 65% m-chloroperbenzoic acid (1.26 g, 4.75 mmol). After 2 hours, the mixture was diluted with EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate, filter and concentrated to afford 1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](O)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C=O)C>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([Cl:21])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a suspension of 2-morpholin-4-yl-5-nitro-benzoic acid (4.0 g, 16 mmol) in toluene were added 2 drops of DMF and thionylchloride (5.7 ml, 79.3 mmol). The mixture was heated to 80° C. for 50 minutes. The solvent was removed in vacuo, and the resulting solid was stirred in ether, filtered and dried to provide the title compound (4.0 g, 93%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:33]([O:32][C:30]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A solution of 35 g (69 mmol) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 380 ml toluene/60 ml THF was treated at −47° C. to −50° C. with 44 g (152 mmol) of a 70% solution of sodium dihydrido-bis(2-methoxy-ethoxo)aluminate in toluene (3.5 M Red-Al in toluene). After 3 h at −50° C. and 1 h at −30° C. the solution was poured into water (1 l) with 40 g of citric acid and extracted with EtOAc (2×). The organic phase was dried over Na2SO4 and evaporated. Column chromatography on silica gel with hexane/EtOAc (7:3) gave 23.0 g (69%) (2S,4R)-2-Hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 476 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:24]=[O:25])C.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([CH:24]=[O:25])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)s1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a stirred solution 5-(4-chlorophenyl)thiophene-2-carboxylic acid (11 g, 0.046 mol) in dry THF (150 ml) was added n-BuLi (63 ml, 0.102 mol, 1.6 M solution in hexane) in a dropwise manner at −78° C. under inert atmosphere. The temperature was slowly raised to 0° C. over a period of 4 h. The reaction mixture was again cooled to −70° C. and dry DMF (34 ml, 0.43 mol) was added slowly. After completion of the addition of DMF, temperature was raised to −10° C. and stirred for 2 h. The reaction mixture was again cooled to −30° C. and 1.5 N HCl (50 ml) was added slowly and reaction was allowed to come to RT. The reaction mixture was extracted with EtOAc (4×200 ml). The combined organic layer washed with water (2×150 ml), brine (2×150 ml), dried (Na2SO4) and concentrated. The crude product washed with p-ether (100 ml) to afford 8 g of the title compound (65%). Rf=0.2 (CHCl3:MeOH, 8:2). This was found pure enough to carry further. Since this intermediate is unstable it has to be used immediately in the next step.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O[CH:8]=[N:9][C:10]1[S:19][C:13]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:12]=2[C:11]=1[C:20](OCC)=[O:21])C>C(O)C>[OH:2][CH2:1][CH2:3][N:4]1[C:20](=[O:21])[C:11]2[C:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:13]=3[S:19][C:10]=2[N:9]=[CH:8]1
Reactant: NCCO
Reactant: CCOC=Nc1sc2c(c1C(=O)OCC)CCN(C)C2
Solvent: CCO
Product: CN1CCc2c(sc3ncn(CCO)c(=O)c23)C1

Procedure:
17.6 ml (292 mmol) of ethanolamine were added to 86.4 g (292 mmol) of 2-ethoxymethyleneamino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 200 ml of ethanol and the mixture was boiled at reflux for 2 h. The mixture was then evaporated in vacuo and the residue was taken up in 30 ml of ethyl acetate while stirring. The solids which precipitated out overnight were filtered off with suction and rewashed with a little ethyl acetate. After recrystallizing from ethanol, 48.0 g (62%) of product having a m.p. of 163-165° C. were isolated.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8](=[O:20])[C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:12]=[C:11](Cl)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:6][O:7][C:8](=[O:20])[C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:12]=[C:11]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH:10]=1
Reactant: COC(=O)c1cc(Cl)nc(S(C)(=O)=O)c1
Reactant: NC1CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NC2CCC2)nc(S(C)(=O)=O)c1
Temperature: 80 °C
Yield: 89.7 %

Procedure:
Add cyclobutylamine (0.13 mL, 1.5 mmol) to a suspension of 2-chloro-6-methanesulfonyl-isonicotinic acid methyl ester (0.25 g, 1.0 mmol), palladium acetate (0.022 g, 0.1 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.062 g, 0.1 mmol), and cesium carbonate (0.325 g, 1.0 mmol) in toluene (5 mL) at room temperature and heat for 16 h at 80° C. Cool, filter through a filtering agent, concentrate and purify (silica gel chromatography, eluting with 15:85 to 40:60 ethyl acetate:hexanes) to give the title compound (0.255 g, 90%).
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)C.C(N(CC)CC)C.Br.[Br:26][C:27]1[CH:28]=[C:29]([CH2:34]Br)[C:30]([NH2:33])=[N:31][CH:32]=1>CN(C=O)C.O>[Br:26][C:27]1[CH:32]=[N:31][C:30]2[NH:33][C:4](=[O:17])[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)[CH2:34][C:29]=2[CH:28]=1
Reactant: CCOC(=O)CNCCCN1CCN(C)CC1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CCCN2CC(=O)Nc3ncc(Br)cc3C2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.7 %

Procedure:
A solution of [3-(4-methyl-piperazin-1-yl)propylamino]acetic acid ethyl ester (1.80 g, 7.41 mmol) and triethylamine (2.3 mL, 16.4 mmol) in DMF (50 mL) was treated with 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (2.57 g, 7.41 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (100 mL) and then extracted with EtOAc (4×100 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 90:10) gave the title compound (0.50 g, 16%) as a colorless oil: MS (ESI) m/e 428 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1.O>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCNS(=O)(=O)c3ccc(CCC(=O)OC)cc3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCNS(=O)(=O)c3ccc(CCC(=O)O)cc3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound obtained in Example 2-11 (100 mg) and lithium hydroxide (17 mg) were added to tetrahydrofuran (4 ml) and water (2 ml) and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added acetic acid (2 ml) and the mixture was concentrated under reduced pressure. The residue was purified by RPHPLC and appropriate fractions were concentrated under reduced pressure to give the titled compound as a white solid. Yield: 40 mg (41%); mp 210-211° C., MS APCI+ve 507 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])[CH2:17][CH2:18]2)=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(COc1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 93.4 %

Procedure:
4-fluoro phenol (95.32 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.293 g, 2.125 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (340 mg, 94.44% yield) as an off-white solid.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]([O-:13])=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Li+].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[CH2:52][CH:51]([C:53]([N:55]2[CH2:61][CH2:60][CH2:59][N:58]([CH:62]3[CH2:65][CH2:64][CH2:63]3)[CH2:57][CH2:56]2)=[O:54])[CH2:50]1>CN(C=O)C>[CH:62]1([N:58]2[CH2:59][CH2:60][CH2:61][N:55]([C:53]([CH:51]3[CH2:50][N:49]([C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[N:10][CH:9]=4)=[O:13])[CH2:52]3)=[O:54])[CH2:56][CH2:57]2)[CH2:65][CH2:64][CH2:63]1
Reactant: CC(C)(O)c1ccc(C(=O)[O-])cn1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(C(=O)N2CC(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Yield: 1.2 %

Procedure:
To a stirred solution of lithium 6-(1-hydroxy-1-methylethyl)pyridine-3-carboxylate (50 mg, 0.28 mmol) and HOBt (42 mg, 0.30 mmol) in DMF (2 mL) was added HBTU, (117 mg, 0.30 mmol) and 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (46 mg, 0.30 mmol). After 20 hours the reaction was absorbed onto an SCX column and the product eluted with 7M NH3. Volatiles were removed at reduced pressure to give the title compound (1.4 mg, 1.2%) after purification by silica FCC (eluting with 90:9:1 Et2O/MeOH/NH3).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:4][CH:3]=1.Cl[CH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C=O)C.C1COCC1.CO>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:29][C:30]4[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2ccc(O)cc2n1Cc1ccc(Br)cc1
Reactant: Cn1ccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc(COc2ccc3nc(CC(C)(C)C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 16.9 %

Procedure:
A mixture of ethyl 3-(1-(4-bromobenzyl)-6-hydroxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (322 mg, 0.75 mmol), 3-(chloromethyl)-1-methyl-1H-pyrazole (97.5 mg, 0.75 mmol) and K2CO3 (310 mg, 2.25 mmol) in DMF (20 mL) was stirred at 50° Celsius for 18 h. The resulting residue was dissolved in THF (9 mL), MeOH (9 mL) and NaOH (2 mL, 5%). The mixture was stirred at 40° Celsius. After 16 h the reaction was concentrated to dryness and the residue was dissolved in water (30 mL), washed with EtOAc (20 mL). The aqueous layer was separated and acidified to pH ˜6 with HCl (6 N) then extracted with DCM (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to dryness and purified by reverse phase HPLC to give the title compound (63 mg, 19%). MS (ESI): mass calcd. for C24H25BrN4O3, 496.11; m/z found, 497.1 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 7.84 (d, J=2.4, 1H), 7.76 (d, J=9.0, 1H), 7.54 (d, J=8.5, 2H), 7.32 (dd, J=9.0, 2.3, 1H), 7.27 (d, J=2.1, 1H), 7.16 (d, J=8.4, 2H), 6.49 (d, J=2.4, 1H), 5.83 (s, 2H), 5.21 (s, 2H), 3.98 (s, 3H), 3.51 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:27])[C:20]=3[O:23]C(C)C)[C@H:15]([CH2:28][NH:29]C=O)[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[ClH:32].B(Cl)(Cl)[Cl:34]>>[ClH:34].[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([C@@H:13]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:27])[C:20]=3[OH:23])[C@H:15]([CH2:28][NH2:29])[O:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2].[ClH:32]
Reactant: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCN(C(=O)OC(C)C)CC1)O[C@H]2CNC=O
Reactant: ClB(Cl)Cl
Agent: Cl
Product: Cc1ccc2c(c1O)C[C@@H](C1CCN(C(=O)OC(C)C)CC1)O[C@H]2CN
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Stir a solution of 4-((1R,3S)-1-formylaminomethyl-5-isopropoxy-6-methyl-isochroman-3-yl)-piperidine-1-carboxylic acid isopropyl ester directly from the previous step in of 5% methanolic hydrochloric acid (4 mL) at room temperature for 2 days. Remove the solvent to give yellow oil. Purify the oil on a 2 g SCX column. The resulting residue was redissolved in 4 mL of anhydrous dichloromethane, cooled to −20° C., and 6 equivalents of BCl3 (using 1M BCl3 in dichloromethane) was added slowly into the solution. After the addition, the reaction mixture was stirred at −20° C. for 2 hours and 0° C. for 1 hour. It was then cooled to −20° C. and quenched with 0.5 mL anhydrous CH3OH. The resulting solution was warmed to room temperature and concentrated. The crude product was purified by 2 g SCX column, followed by 1 g silica gel column (eluted by 7N NH3 in methanol:ethyl acetate=1:10) and the hydrochloride was formed with 2M HCl in diethyl ether. CIMS 363.2 (MH+), tR (min)=2.65.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1.CCOCC.O>CS(C)=O>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CC1CCCCN1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CC1CCCCN1c1ccc(C#N)cc1C(F)(F)F

Procedure:
4-fluoro-3-(trifluoromethyl)benzonitrile (Combi-blocks, 50 g; 264.40 mmol) and 2-methylpiperidine (Acros, 156.08 mL; 1 321.98 mmol) in DMSO (500 mL) were heated at 100° C. under nitrogen for 12 h. After this time, Et2O and water were added to the reaction mixture and organic phase was washed with water, NaHCO3 and a saturated aqueous solution of NH4Cl successively. Organics were dried over MgSO4, evaporated under vacuum to give the title compound as a beige powder. 1H NMR (DMSO-d6) δ 8.19 (d, J=2 Hz, 1H), 8.12 (dd, J=8.4, 2 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 3.15-3.10 (m, 1H), 2.90-2.85 (m, 1H), 2.60-2.51 (m, 1H), 1.77-1.25 (m, 6H), 0.72 (d, J=6.0 Hz, 3H). LC/MS (Method B): 269.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[F:8][C:6]1[CH:5]=[C:4]([CH:9]([C:28]2[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(C(=O)/C=C/c2cc(F)cc(F)c2)ccc1=O
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2cc(F)cc(F)c2)ccc1=O

Procedure:
In analogy to example 203, step 1, (E)-5-(3-(3,5-difluorophenyl)acryloyl)-1-methylpyridin-2(1H)-one was reacted with 4-(methylsulfonyl)phenylboronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a yellow solid, MS (ESI+): m/z=432.3 [M+H]+.