Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:12]12[O:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][NH:14][CH2:13]2.[OH-].[Na+]>O>[C:1]1([CH2:7][C:8]([N:14]2[CH2:13][CH:12]3[O:19][CH:16]([CH2:17][CH2:18]3)[CH2:15]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Cc1ccccc1)N1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenylacetyl chloride (15.46 grams, 0.1 mole) (Aldrich Chemical Co., Inc., Milwaukee, Wisconsin) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane hydrochloride (product of Example 3) (14.96 grams, 0.1 mole) and sodium hydroxide (10 grams) in 300 ml water at 10° C. After the addition of phenylacetyl chloride, the reaction mixture was stirred at room temperature for 2 hours. The crystalline solid (22.1 grams, 95.6%) which separated was filtered off, washed with water, and finally recrystallized from a blend of about 30% petroleum ether (boiling point 30°-60° C.) and 70% diethyl ether (v/v) to yield the product 3-phenylacetyl-8-oxa-3-azabicyclo(3.2.1)octane which had a melting point of 106°-106.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:4]1>Cl>[CH3:1][N:2]([CH3:19])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: COC(=O)c1ccc(CN2CC[C@@H](N(C)C)C2)cc1
Agent: Cl
Product: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Temperature: -78 °C
Yield: 124.6 %

Procedure:
Compound 6 (0.55 g, 2.1 mmol) was heated to 110° C. in 2N aqueous hydrochloric acid (7 mL) for 18 h then cooled to −78° C. and lyophilized to give compound 7 as a grey solid (0.65 g, 97% yield). LRMS: 248.2 (calc), 249.0 (obs).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([O:15]CC)=[O:14])[CH2:10][NH:9][C:8]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>CN(C=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:9]2[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[O:12][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:18][C:8]2=3)=[CH:32][CH:33]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CCOC(=O)C1CNc2cc(OC(F)(F)F)ccc2O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(C(=O)O)Oc3ccc(OC(F)(F)F)cc32)cc1
Temperature: 60 °C
Yield: 58.4 %

Procedure:
Ethyl 6-(trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (775 mg, 2.66 mmol) was dissolved in DMF (4 mL) containing K2CO3 (1103 mg, 7.98 mmol), sodium iodide (80 mg, 0.53 mmol). 1-(Bromomethyl)-4-methoxy-benzene (1070 mg, 776 μL, 5.32 mmol) was added slowly to the above reaction mixture. The mixture was heated at 60° C. for 6 h. After evaporation of the solvent, the residue was treated with water and extracted with dichloromethane. The organic extracts were dried over Na2SO4 and evaporated in vacuo. The residue was chromatographed over a silica gel column (0-25% ethyl acetate/hexanes) to provide 4-(4-methoxybenzyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (639 mg, 1.553 mmol, 58.37%) as a white solid. LC/MS m/z 412.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 7.18 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.6, 2H), 6.86 (d, J=8.6 Hz, 1H), 6.68 (d, J=2.1 Hz, 1H), 6.54 (d, J=8.7 Hz, 1H), 5.09 (t, J=3.3 Hz, 1H), 4.45 (d, J=15.4 Hz, 1H), 4.29 (d, J=15.3 Hz, 1H), 4.16-4.05 (m, 2H), 3.73 (s, 3H), 3.52-3.42 (m, 2H), 1.13 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH3:10][NH:11][CH2:12][CH2:13][CH3:14].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:10][N:11]([CH2:12][CH2:13][CH3:14])[C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: CCCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C)C(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Pyrazine carboxylic acid (1.00 g, 8.06 mmol) was dissolved in DMF (5 mL), and methylpropylamine (99 μL, 9.69 mmol), WSC.HCl (1.85 g, 9.69 mmol), and HOBt.H2O (1.48 g, 9.69 mmol) were added thereto, and then, the mixture was stirred at room temperature for 1 hour. To the mixture, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50) to give N-methyl-N-propylpyrazinecarboxamide (1.41 g, 7.86 mmol, yield: 98%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]#[C:15][Si](C)(C)C)[CH:11]=[CH:12][CH:13]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:9]=1)#[CH:15]
Reactant: COCCOCOc1cccc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#Cc1cccc(OCOCCOC)c1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
[3-(2-Methoxy-ethoxymethoxy)-phenylethynyl]-trimethyl silane (0.57 g, 2 mmol, example 97) and 1.0 M tetrabutylammonium fluoride (2.1 mL, 2 mmol) are added to THF (10 mL) and acetic acid (0.13 g, 2 mmol) is added and this mixture is stirred at 20° C., under nitrogen. After 15 minutes, the solvent is removed in vacuo and the residue is azeotroped with benzene and purified by flash chromatography (silica, 20% ethyl acetate, 30% dichloromethane in hexanes) to give 1-ethynyl-3-(2-methoxy-ethoxymethoxy)-benzene (0.28 g, 1.4 mmol) which is dissolved in THF (8 mL), cooled to −78° C., under nitrogen and to this solution is added 2.5M n-butyl lithium (0.56 mL, 1.4 mmol) dropwise over 30 seconds. After stirring for 15 minutes, 1.0M zinc chloride in ether (1.4 mL, 1.4 mmol) is added dropwise over 30 seconds and this mixture is stirred for 30 minutes. Bis-(dibenzylideneacetone) palladium (0.04 g, 0.07 mmol) and bis (diphenyl phosphino) ferrocene (0.04 g, 0.07 mmol) is added and to this mixture is added ethyl-2-methyl-6-trifluoromethanesulfonyloxy benzoate (0.44 g, 1.4 mmol, 95) in THF (2 mL). The cooling bath is removed and the reaction allowed to warm to room temperature. Then the reaction mixture is heated in an oil bath at 65° C. overnight. The reaction is then diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride and brine and then dried over magnesium sulfate. The solvent is removed in vacuo and the residue purified by flash chromatography (silica, 10% ethyl acetate, 25% dichloromethane in hexanes) to give the title compound. MS (ESI) 369 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH2:22])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:21][NH:22][C:32](=[O:33])[CH2:31][C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(I)cc2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)Cc2cc(F)cc(F)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a stirred solution of 4-aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.24 mmol) in CH2Cl2 (0.5 mL) at room temperature under Ar was added a solution of 3,5-difluorophenylacetyl chloride (0.28 mL of a 1 M solution in CH2Cl2, 0.28 mmol) followed by pyridine (0.25 mL). The mixture was stirred at room temperature for 16 h then diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and saturated brine (5 mL) and dried over Na2SO4. Filtration and rotary evaporation gave the crude 4-{[2-(3,5-difluoro-phenyl)-acetylamino]-methyl}-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.09 g, ˜65%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:31][C:32]1[CH:33]=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1[F:38]>O1CCCC1.[Cl-].[Na+].O>[F:31][C:32]1[CH:33]=[C:34]([S:39]([N:11]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:40])=[O:41])[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: O=Cc1c[nH]c(-c2ccccn2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccn2)n(S(=O)(=O)c2ccc(F)c(F)c2)c1
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution (16 mL) of 5-(pyridin-2-yl)-1H-pyrrole-3-carbaldehyde (80 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 56 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (307 mg) was added dropwise and the mixture was stirred for 30 min, 3,4-difluorobenzenesulfonyl chloride (198 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1), and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 114 mg, 70%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH:40]1[CH2:45][CH2:46]O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([N:39]1[CH:40]2[CH2:41][N:42]([CH2:46][CH2:45]2)[CH2:43][CH2:44]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCCC1CNCCN1Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3CCC2C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
Diethyl azodicarboxylate (15.8 mL, 100 mmol) was slowly added to a solution of triphenylphosphine (26.2 g, 100 mmol) in THF (200 mL) while maintaining the reaction temperature below 20° C. After stirring this mixture for 30 min at RT, a solution of 2-(1-benzyl-piperazine-2-yl)-ethanol (11 g, 50 mmol) in THF (100 mL) was added while maintaining the reaction temperature below 20° C. The reaction mixture became turbid and the solvent was removed in vacuo after a period of 1 h. The residue was partitioned between water (20 mL) and ethyl acetate (50 mL) and the pH was adjusted to 2 with 6 N HCl. The phases were separated and the aqueous phase was extracted with EtOAc (50 mL) at pH 3.0, 4.5 and 10 (4×). The pH 10 extracts were combined, dried (Na2SO4), filtered and concentrated to an oil. The oil was triturated three times with hot hexanes (100 mL) to remove any remaining triphenylphosphine and triphenylphosphine oxide and the hexanes were decanted. The remaining oil was dried resulting in 7.5 g (74%) of the title compound: APCI MS m/z 203.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][NH:15]C(OC(C)(C)C)=O)=[O:13]>C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][NH2:15])=[O:13]
Reactant: CC(C)(C)OC(=O)NNC(=O)NCCSSc1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)NCCSSc1ccccn1

Procedure:
In a first embodiment, a novel bifunctional compound was prepared by first reacting methoxycarbonylsulfenyl chloride with 2-aminoethanethiol hydrochloride, then 2-mercaptopyridine to form 2-[(2-pyridinyl)dithio]ethanamine hydrochloride (see FIG. 2). This compound was then reacted with phosgene in the presence of triethylamine (TEA), then t-butyl carbazate, to form N-[2-[(2-pyridinyl)dithio]ethyl]-2-(tert.-butoxy-carbonyl)hydrazinecarboxamide. The hydrazinecarboxamide was next dissolved in TFA to form N-[2-[(2-pyridinyl)dithio]ethyl]hydrazinecarboxamide, compound 10, a semicarbazide, which was then reacted with adriamycin hydrochloride to form the semicarbazone derivative of ADM containing a reactive pyridinyldithio moiety, compound 1, FIG. 1.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:21][C@:20]([OH:26])([C:22]([O:24][CH3:25])=[O:23])[N:19]3[C:9]4=[C:10]([C:13]5[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:11][CH2:12][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2.Cl.[O:28]=[C:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:30]([OH:32])=[O:31].C(=O)(O)[O-].[Na+]>O>[CH3:1][CH2:2][C@:3]12[CH2:21][C@:20]([OH:26])([C:22]([O:24][CH3:25])=[O:23])[N:19]3[C:9]4=[C:10]([CH2:11][CH2:12][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=13.[O:28]=[C:29]([CH2:33][CH2:34][C:35]([O-:37])=[O:36])[C:30]([O-:32])=[O:31]
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: O=C([O-])CCC(=O)C(=O)[O-]

Procedure:
650 ml. of vincamine hydrochloride (1.66 millimole) are dissolved in 10 ml. of water, and, after vibration, a solution of 248 mg. (1.73 millimole) of 2-ketoglutaric acid and 145 mg. of sodium bicarbonate in 3 ml. of water is added. After being allowed to stand and cool, 453 mg. of vincamine 2-ketoglutarate are obtained. The resulting solution is concentrated in a rotary evaporator to one third of the original volume and, after cooling, an additional amount of 287 mg. of salt are obtained. A total of 740 mg. of salt is thus obtained, that is to say, a yield of 89%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[C:7]2=O>O.NN>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[CH2:7]2
Reactant: CN1C(=O)C(=O)c2cccc(F)c21
Agent: NN
Solvent: O
Product: CN1C(=O)Cc2cccc(F)c21
Temperature: 0 °C

Procedure:
7-Fluoro-1-methyl-1H-indole-2,3-dione (6, 2.48 g, 0.0138 mol) is heated with neat hydrazine hydrate (30 ml) at 130° C. for 30 minutes. The mixture is cooled, diluted with ice water and extracted with ethyl acetate. The extract is washed with brine, dried (Na2SO4), and evaporated to give the title compound as a solid. HPLC r.t. 4.07 min; MS for C9H8FNO m/z 165.16 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:43])[CH:10]=1)#[N:2].[CH3:44][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[F:43][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:42])[N:18]([C@H:28]2[CH2:29][CH2:30][C@H:31]([O:34][CH2:35][CH:36]([OH:37])[CH3:44])[CH2:32][CH2:33]2)[C:19]2[N:20]([N:25]=[CH:26][CH:27]=2)[C:21]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reaction time: 1 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.30 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.73 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (6 mL), and sodium borohydride (0.020 g) was added at 0° C. After stirring at 0° C. for 30 min, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.28 g, 99%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].[Cl-].C(N(CC)CC)C>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C=O)C.O>[C:7]1([CH2:6][CH:2]([NH:1][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C(Cc1ccccc1)Nc1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To a solution of (S)-2-amino-3-phenylpropanoic acid (1.52 g, 9.12 mmol) in a DMF/H2O mixture (10/1, 16.5 mL) maintained under nitrogen flowstream, iodobenzene (1.00 mL, 9.12 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (357 mg, 0.42 mmol) CuI (86.4 mg, 0.42 mmol), K2CO3 (1.21 g, 9.12 mmol), rimethylbenzylammonium chloride (286 mg, 1.51 mmol) and triethylamine (TEA) (2.50 mL, 18.0 mmol) are added and the mixture stirred for 24 hours at 100° C. under nitrogen flowstream (LC-MS monitoring: complete conversion). The reaction mixture is partitioned between EtOAc and water; 1N HCl is added until pH=1 and the organic layer is separated, washed with brine and dried over Na2SO4. The resulting crude is purified by flash chromatography (DCM/MeOH=99/1) and 1.21 g of I21 is obtained (56% yield).
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([S:7][CH2:8]Cl)([CH3:6])[CH3:5].[P:15]([S-:21])(=[S:20])([O:18][CH3:19])[O:16][CH3:17].[Na+]>>[P:15]([S:21][CH2:8][S:7][C:4]([CH3:6])([CH3:5])[C:3]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:2]=1[Cl:1])(=[S:20])([O:18][CH3:19])[O:16][CH3:17]
Reactant: COP(=S)([S-])OC
Reactant: CC(C)(SCCl)c1cccc(Cl)c1Cl
Agent: [Na+]
Product: COP(=S)(OC)SCSC(C)(C)c1cccc(Cl)c1Cl

Procedure:
Using chloromethyl 2,3-dichloro-α,α-dimethylbenzyl sulfide (prepared from 2,3-dichloro-α,α-dimethyl-α-toluenethiol obtained as in Example 1 from 2,3-dichloro-α,α-dimethylbenzyl alcohol) and stirring vigorously for 2 hours at 50° C. with a 10% excess of 50% aqueous sodium O,O-dimethyl phosphorodithioate solution gives a crude product which is purified as in Example 6 to give the pure, desired product as a colorless oil.
Reaction SMILES: CC1C=C(C)N(C2C=C(C=CC=2)OC2C=CC3C4C(=CC=CC=4)NC=3C=2)N=1.CC1C=C(C)N(C2C=C(C=CC=2)[O:38][C:39]2[CH:51]=[CH:50][C:49]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:42]([CH:52]4[CH2:57][CH2:56][CH2:55][CH2:54][O:53]4)[C:41]=3[CH:40]=2)N=1.S(O)(C)(=O)=O.C(=O)(O)[O-].[Na+]>CO.CCCCCC.C(OCC)(=O)C>[O:53]1[CH2:54][CH2:55][CH2:56][CH2:57][CH:52]1[N:42]1[C:41]2[CH:40]=[C:39]([OH:38])[CH:51]=[CH:50][C:49]=2[C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2
Reactant: Cc1cc(C)n(-c2cccc(Oc3ccc4c5ccccc5n(C5CCCCO5)c4c3)c2)n1
Agent: CS(=O)(=O)O
Agent: Cc1cc(C)n(-c2cccc(Oc3ccc4c(c3)[nH]c3ccccc34)c2)n1
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Oc1ccc2c3ccccc3n(C3CCCCO3)c2c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In another step, 2-[3-(3,5-Dimethylpyrazol-1-yl)-phenoxy]-carbazole was synthesized. To a 50 mL round flask was added with the solution of 2-[3-(3,5-Dimethylpyrazol-1-yl)-phenoxy]-N-(tetrahydropyranyl)carbazole (0.49 g, 1.12 mmol) and MsOH (0.36 mL, 5.6 mmol) in methanol (20 mL), and the mixture was kept at rt for 30 minutes then 50° C. for 1.5 hours. TLC showed that all the protected starting material was transferred, and then trace sodium bicarbonate was added into the system to quench the reaction. The resulting product was directly treated with an flash column using hexane/ethyl acetate=3:1 as eluent to give N-tetrahydropyranyl-2-hydroxycarbazole as a white solid. (0.32 g, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][O:35][CH3:36])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][O:35][CH3:36])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: COCCC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
66 mg (0.11 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}4-methoxybutanoyl)amino]benzoate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 31 mg (52% of theory)
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13]C(=O)OC(C)(C)C)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH2:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of tert-butyl (trans-2-(4-cyclopropylphenyl)cyclopropyl)carbamate (260 mg, 0.951 mmol) in dichloromethane (DCM) (3 mL) was added TFA (500 μA, 6.49 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give 148 mg of product as pale yellow oil. MS: (M+H)+=174.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.57-0.70 (m, 2H), 0.86-1.04 (m, 4H), 1.78-1.93 (m, 2H), 2.37-2.48 (m, 1H), 6.86-7.00 (m, 4H).