Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=[CH:15][C:16]#N)=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.C([O-])=[O:26].[NH4+].O.C(O)(=O)C>[Ni].C(O)C>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:15][CH:16]=[O:26])=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: O=C[O-]
Agent: [Ni]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
In a 200 mL-volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed under nitrogen atmosphere 4.0 g (12.7 mmol) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile (prepared in Reference Example 1), 1.6 g (25.4 mmol) of ammonium formate, 4.4 g (37.5 mmol as nickel atom) of water-containing developed Raney-nickel (NDHT-90, nickel content 50 wt. %, available from Kawaken Fine Chemical Co., Ltd.), and 40 mL of acetic acid. The content was reacted at 65° C. for 4 hours. After the reaction was complete, the content was cooled to room temperature. After addition of 20 mL of ethanol, the catalyst was removed by filtration using a celite. The filtrate was concentrated under reduced pressure, and 40 mL of ethyl acetate was added. The mixture was washed successively with 5 mL of hydrochloric acid (1 mol/L), 10 mL of water, 20 mL of aqueous sodium hydroxide solution (1 mol/L), 14 mL of an aqueous alkaline DL-tartaric acid solution (1.0 g of DL-tartaric acid was dissolved in 1 mol/L aqueous sodium hydroxide solution), and 20 mL of saturated aqueous sodium chloride solution. The organic portion was dried over anhydrous magnesium sulfate. The organic portion was filtered and concentrated under reduced pressure, to obtain 3.4 g (yield 82%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enal as a pale yellow crystalline product (purity 98%, in terms of an area percent according to high performance liquid chromatography).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][O:17][S:18](=[O:21])(=[O:20])[OH:19].[OH-].[Na+]>O>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:14][CH2:15][CH2:16][O:17][S:18](=[O:20])(=[O:19])[OH:21])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCCOS(=O)(=O)O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCCOS(=O)(=O)O)c1
Reaction time: 1 h
Yield: 93.5 %

Procedure:
221.5 g of 3-nitro-benzenesulphonyl chloride are introduced in portions into a solution of 150 g of sulphuric acid mono-2-amino-ethyl ester and 0.6 liter of water at 60°-70° C. During this procedure, the pH value is continuously kept between 9.0 and 10.0 by adding 45% strength sodium hydroxide solution dropwise. The mixture is subsequently stirred at 60°-70° C. and pH 9.0 to 10.0 for 1 hour and then allowed to cool and the resulting precipitate is filtered off. The precipitate is washed with water and dried at 80° C. 305 g of sulphuric acid mono-N-(3-nitro-benzenesulphonyl)-2-amino-ethyl ester are obtained. This ester is dissolved in 1.5 liters of dimethylformamide and hydrogenated over Raney nickel. After subsequently filtering off the catalyst and distilling off the solvent in vacuo, about 220 g of sulphuric acid mono-N-(3-aminophenylsulphonyl)-2-aminoethyl ester are obtained. ##STR16##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]([CH3:28])[CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:27][C:24]1[CH:23]=[N:22][C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:28])[CH3:16])=[CH:26][CH:25]=1
Reactant: CN(C)CCNc1ccc(N)cn1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(NCCN(C)C)nc1
Yield: 74.7 %

Procedure:
Following General procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (284 mg, 1 mmol) was reacted with N2-(2-(dimethylamino)ethyl)pyridine-2,5-diamine (270 mg, 1.5 mmol) to afford the desired product (320 mg, 74%) as a yellow solid: ESI MS m/z 428 [C20H22BrN5O+H]+.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO.C1COCC1>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[N:22]=[CH:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
785 mg (1.5 mmol) of 2-[5-(1-trityl-1H-imidazol-4-yl)pent-4-enyl]isoindole-1,3-dione, 10 ml of a MeOH/THF mixture (6/4) and 392 mg of 10% Pd/C are introduced into a Parr bomb. The reaction medium is stirred at room temperature under a hydrogen pressure of 5 bar. After 4 hours, the reaction medium is filtered through Celite and concentrated. The crude product obtained is chromatographed on silica gel (eluent: heptane/EtOAc (5/5) and then CH2Cl2/MeOH (9/1)). 380 mg of 2-[5-(1-trityl-1H-imidazol-4-yl)pentyl]isoindole-1,3-dione in the form of a white powder are obtained in a yield of 48%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([NH2:11])=O)=[N:6][C:7]=1[CH3:8].COC(OC)[N:15]([CH3:17])C.[NH2:20]N>C(O)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([C:9]2[N:11]=[CH:17][NH:15][N:20]=2)=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1nc(C(N)=O)ccc1Br
Reactant: NN
Solvent: CC(=O)O
Product: Cc1nc(-c2nc[nH]n2)ccc1Br
Temperature: 85 °C
Reaction time: 5 h

Procedure:
5-Bromo-6-methylpicolinamide (1 g, 4.65 mmol) and N,N-dimethylformamide dimethylacetal (20 mL) were combined in a 100 mL round-bottom flask with a stir bar and heated at 85° C. under a reflux condenser under nitrogen for 3 h. The resulting mixture was concentrated under reduced pressure and dried under vacuum to give yellow oil, which was used in the next step without purification. The residue was diluted with acetic acid (10 mL) and hydrazine (2.5 mL, 70.3 mmol) was added drop-wise and allowed to stir at room temperature for 5 h. The reaction mixture was poured into ice water. The resulting solid was filtered, washed with water and dried to give the desired product as a white solid. The aqueous filtrate was extracted with dichloromethane. The organic layer was concentrated under reduced pressure nearly to dryness to yield additional material. Combination of two batches gave the desired product (0.7 g, 2.9 mmol, 63% yield). MS (ESI) m/z 241.1 [M+2]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:27]=[C:28]([N:40]([CH3:44])[C:41](=[O:43])[CH3:42])[CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:45][C:46]([F:51])([CH3:50])[C:47](O)=[O:48].CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([N:40]([CH3:44])[C:28]1[CH:29]=[CH:30][C:31]([NH:32][CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[C:26]([NH:25][C:47](=[O:48])[C:46]([F:51])([F:45])[CH3:50])[CH:27]=1)(=[O:43])[CH3:42]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(NC(=O)C(C)(F)F)c1
Reaction time: 8 h

Procedure:
HATU (1.44 g, 3.78 mmol) and N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N-methylacetamide (1.00 g, 3.60 mmol) (for preparation, see Example 1, steps B to E) were added to a solution of 2,2-difluoropropanoic acid (0.40 g, 3.60 mmol) and DIPEA (0.75 mL, 4.32 mmol) in DMF (100 mL) at room temperature. The reaction mixture was stirred overnight. The solvent was concentrated and the crude product was recovered in EtOAc. The organic was washed with water, saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was concentrated giving the title compound that was used for the next step without further purification. Yield: 1.00 g (75%); MS (ESI) (M+H)+: 370.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=[N:10]1.[Br:19]Br.O>C(O)(=O)C>[Br:19][C:12]1[CH:11]=[N:10][N:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: BrBr
Reactant: CCOC(=O)c1ccnn1-c1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(Br)cnn1-c1c(Cl)cccc1Cl
Reaction time: 60 h

Procedure:
14.3 g of ethyl 1-(2,6-dichlorophenyl)-pyrazole-5-carboxylate from Example 4 were dissolved in 100 ml of glacial acetic acid, 10 g of Na acetate were added, and 4.5 g of bromine were added dropwise at room temperature. After 60 hours, the reaction mixture was poured into 1 liter of water, washed with water and recrystallized from ethanol. Yield: 8.2 g Melting point: 62°-65° C.
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>[Fe].O>[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH2:19])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(F)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To an ethanol (25 mL)-water (25 mL) mixture containing 2-(benzyloxy)-4-fluoro-1-nitrobenzene obtained were added iron (2.79 g, 50.0 mmol) and ammonium chloride (535 mg, 10.0 mmol) at room temperature, and the mixture was stirred at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford the title compound as a brownish red oil (1.26 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.[C:19](=O)([O-])[O-].[K+].[K+].C[CH:26]=[CH:27][CH2:28][NH2:29]>O1CCCC1.O>[OH2:6].[CH3:19][N:29]([CH2:28][CH:27]=[CH2:26])[C:11]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH2:8]1)=[O:12]
Reactant: CC=CCN
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(C)C(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.25 h

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 0.72 g (0.01 mole) of N-methylallylamine. After stirring for 15 minutes, a piece of ice was added and stirring continued for 15 hr. The reaction mixture was diluted with water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo (3.7 g). The crude oil was chromatographed on a 75 g silica gel column by eluting with chloroform. After the first crude material was washed from the column the three product fractions were combined and concentrated in vacuo, to yield 3 g (97%) of water-like oil.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])[CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH2:7][C:6]1=[O:25])(O)=[O:2].[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].ON1C2C=CC=CC=2N=N1.O>CN(C=O)C>[F:26][C:27]([F:35])([F:36])[C:28]1[CH:29]=[C:30]([NH:31][C:1]([CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:24])[CH:11]=[CH:12][C:13]=3[O:15][CH3:16])[CH2:8][CH2:7][C:6]2=[O:25])=[O:2])[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC(=O)O)C(=O)CC2
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC(=O)Nc1cccc(C(F)(F)F)c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg of 5-(1-carboxymethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione was dissolved in 5 ml of DMF. 0.35 ml of 3-trifluoromethyl aniline, 0.32 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(WSC), and 0.25 g of 1-hydroxybenzotriazole (HOBT) were added to the solution, followed by stirring at room temperature overnight. Water was added to the reaction liquid, and the solid thus obtained was separated by filtration. The solid was dissolved in methylene chloride, washed with sodium chloride solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1), giving 412 mg of 5-{1-[N-(3-trifluoromethylphenyl)amino]carbonylmethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=1.[H-].[Na+]>CN(C)C=O>[CH3:23][N:15]([C:13]1[CH:14]=[C:9]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=[CH:11][C:12]=1[N+:24]([O-:26])=[O:25])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccccn2)ccc1[N+](=O)[O-]
Yield: 39.1 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2-mercaptopyridine (0.89 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.29 g), sodium hydride (55 wt. %, 0.11 g) and anhydrous N,N-dimethylformamide (40 ml) and the reaction mixture was purified to give the title compound (1.13 g).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[NH:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.C([O:30][CH:31]=[C:32]([C:38](OCC)=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34])C>FC(F)(F)C(O)=O>[CH2:19]([C:18]1[N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[C:6]([OH:5])=[O:7])=[CH:15][CH:14]=2)[C:31](=[O:30])[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][N:23]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCCC(=N)NCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound is prepared form N-(2'-t-butoxycarbonylbiphen-4-yl)methylvaleramidine and diethyl ethoxymethylenemalonate (Aldrich) similarly to that in Example 7. The t-butyl ester is hydrolyzed in neat trifluoroacetic acid to give the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].O.C([O-])(O)=O.[Na+].[Br:10][C:11]1[C:12]([CH2:17][C:18]#[N:19])=[N:13][CH:14]=[CH:15][CH:16]=1>C(O)C>[Br:10][C:11]1[C:12]([CH2:17][C:18]([NH:2][OH:3])=[NH:19])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1ncccc1Br
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(Cc1ncccc1Br)NO
Temperature: 25 °C

Procedure:
A vigorously stirred mixture of hydroxylamine hydrochloride (924 mg, 13.3 mmol), water (4 mL), NaHCO3 (1.12 g, 13.3 mmol), 3-bromo-2-cyanomethylpyridine (Intermediate 1) (1.31 g, 6.65 mmol) and ethanol (14 mL) was heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature, the ethanol was removed in vacuo and the white solid collected by filtration, washing with water (3×10 mL). The wet solid was dried in vacuo at 40° C. for 1 hour to yield 2-(3-Bromo-pyridin-2-yl)-N-hydroxy-acetamidine as a solid (Intermediate 2).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CS(C)=O.O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 160 °C
Reaction time: 2 h
Yield: 121.8 %

Procedure:
In 120 mL of dimethyl sulfoxide were suspended 54.54 g (168 mmol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 30.00 g (112.2 mmol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate and 11.82 g (112.2 mmol) of sodium carbonate, heated to 160° C. and stirred for 2 hours. After cooling to room temperature, 300 mL of ethyl acetate and 300 mL of water were added and separated into two layers. The organic layer was washed twice with 150 mL of water and concentrated under reduced pressure. The residue was subjected to alumina chromatography to be eluted with ethyl acetate. The desired fraction was collected and concentrated to provide 75.96 g of the crude title compound. HPLC purity area percentage 70.5%, Yield 85%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:11]1[CH:16]=CC=C[N:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1NC>[Cu]I.CCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:27]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:16][CH2:11][NH2:12])=[CH:2]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: Clc1ccccn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: NCCc1cn(-c2ccccc2)c2ccccc12
Yield: 410.5 %

Procedure:
Using the general procedure, indole (0.117 g, 1.00 mmol) was coupled with 2-chloropyridine (113 μL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (32 μL, 0.20 mmol, 20 mol %) and toluene (1.0 mL) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 9:1) provided 0.194 g (100% yield) of the product as a yellow oil. 1H NMR (400 MHz, CDCl3): δ9.24 (s, 1H), 9.05 (s, 1H), 8.41 (s, 1H), 7.75 (m, 2H), 7.60 (m, 2H), 7.48 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].[Cl:18][C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([N:28]=[C:29]=[O:30])=[C:21]([CH:31]([CH3:33])[CH3:32])[CH:20]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:31]([CH3:33])[CH3:32])[C:22]([NH:28][C:29]([NH:17][S:14]([C:3]2[CH:4]=[C:5]([C:8]3([CH3:13])[O:12][CH2:11][CH2:10][O:9]3)[CH:6]=[CH:7][C:2]=2[F:1])(=[O:16])=[O:15])=[O:30])=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=1
Reactant: CC1(c2ccc(F)c(S(N)(=O)=O)c2)OCCO1
Reactant: CC(C)c1cc(Cl)cc(C(C)C)c1N=C=O
Product: CC(C)c1cc(Cl)cc(C(C)C)c1NC(=O)NS(=O)(=O)c1cc(C2(C)OCCO2)ccc1F

Procedure:
3-(2-Fluoro-5-(2-methyl-[1,3]dioxolan-2-yl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 168-170° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH3:10].[NH2:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:15]1[C:14]2[C:13](=[CH:21][C:20]([Cl:22])=[CH:19][CH:18]=2)[N:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]=1[CH3:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: CCC(=O)c1ccccc1F
Product: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1Cl

Procedure:
Prepared according to Procedure J using 1-(2-fluorophenyl)propan-1-one and 2-amino-4-chlorobenzoic acid in phosphorous oxychloride to afford a colorless solid upon purification by chromatography on silica gel. Mass Spectrum (ESI) m/e=305.9 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:2][CH3:1]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Reactant: CN
Product: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.2 %

Procedure:
5.1 g of methylamine is condensed in a solution of 6.8 g of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one in 35 ml of anhydrous tetrahydrofiran at -78° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at -20° C., it was allowed to reach room temperature to be able to evaporate excess methylamine. Then, the reaction solution is added to saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 6.7 g of 11β-fluoro-3-hydroxy-7α-[5-(methylamino)-pentyl]-estra-1,3,5(10)-trien-17-one is obtained as crude product.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]1)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]([O:10][CH3:9])=[O:12])[CH2:18][CH2:17]1)=[O:20]
Reactant: O=C1CCC(=O)N1O
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)ON2C(=O)CCC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-hydroxysuccinimide (6.18 g, 0.0537 mol) and trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (10.00 g, 0.05370 mol) in THF (100.00 mL) was charged with (N,N′-dicyclohexylcarbodiimide (11.08 g, 0.0537 mol) in THF (16 mL). This reaction was stirred at rt for an additional 16 h then stirred at 45° C. for 1 h. The reaction mixture was filtered while still warm through a fitted funnel. The cake was washed with 3 more portions of THF and the filtrate was concentrated in vacuo and was crystallized from i-PrOH (300 mL) and filtered through a fitted funnel resulting in 11.8 g, (78% yield) of the title compound as a white crystals. 1H NMR (400 MHz, CDCl3) δ ppm 1.45-1.69 (m, 4H), 2.07-2.16 (m, 2H), 2.18-2.28 (m, 2H), 2.29-2.39 (m, 1H), 2.59-2.71 (m, 1H) 2.84 (br. s., 4H) and 3.68 (s, 3H); MS (ES+): m/z 284.09 [MH+].