Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO.Cl.C(O)(C)C.C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(COc1cc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12)N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Nc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3ccccc3n2)cc1
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
4-{[2-(4-Nitrophenyl)-4-quinolyl]oxyacetyl}morpholine (3.93 g), prepared according to Example 31, dissolved in methanol (80 cc) is hydrogenated at 40° C. for 30 minutes and then at room temperature (approximately 20° C.) and under atmospheric pressure in the presence of a 5N solution (4 cc) of hydrochloric acid in isopropanol and palladinized charcoal (10% Pd) (0.4 g) as catalyst. After absorption of the theoretical amount of hydrogen, normal sodium hydroxide solution (25 cc) is added to the reaction mixture in order to redissolve the precipitate formed. After filtration, the solvent is removed under reduced pressure and the residual aqueous phase is taken up with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue (2.9 g) is dissolved in hot ethyl acetate (15 cc); ethyl ether (30 cc) is then added, and the precipitate is filtered off and chromatographed on silica gel using a toluene/methanol/diethylamine (90:5:5 by volume) mixture. 4-{[2-(4-Aminophenyl)-4-quinolyl]oxyacetyl}morpholine (1.05 g), m.p. 174° C., is thereby isolated.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])(=[O:26])[NH2:25]>>[NH2:25][C:24](=[O:26])[CH2:27][CH2:28][CH2:29][C:30]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:31]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: NC(=O)CCCC(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCCC(N)=O

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethyny-octahydro-indole-1-carboxylic acid methyl ester and 4-carbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-amino-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=427; RT=1.01 min; UPLC Method I
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[NH2:11][CH2:12][CH2:13][SH:14]>CO.C[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:14][CH2:13][CH2:12][NH2:11])=[CH:5][CH:4]=1
Reactant: NCCS
Reactant: COc1ccc(CCl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CSCCN)cc1
Yield: 95.7 %

Procedure:
4-Methoxybenzyl chloride (15.6 g) was reacted with 2-aminoethanethiol (7.7 g) in methanol and sodium methoxide, to afford of 2-(4-methoxybezyl-sulfanyl)-ethylamine (1) (18.8 g). One half of this material was taken in dichloromethane (cooling bath 0° C.). Chloroacetyl chloride in the same solvent, was added slowly with stirring, followed by an equivalent of triethyl amine to produce 2-chloro N-[2-(4-methoxybenzyl-sulfanyl)-ethyl]acetamide (2) in a 94% yield. Compound 2 was reacted with an equivalent amount of 1 in refluxing acetonitrile for 6 hrs to provide N-[-2-(4-methoxy-benzylsulfanyl)-ethyl]-2-[2-(4-methoxy-benzylsulfanyl)-ethylamino]-acetamide (3) (40.4 g). Compound 3 was reduced with lithium aluminium hydride (LAH) to yield 4 in 85%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-:17][Mn](=O)(=O)=O.[K+].[OH-].[K+]>O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:17])=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1c(C=O)c(=O)n(-c2ccccc2)n1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Temperature: 75 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a mixture of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde (2 g, 9.25 mmol) in water (100 mL) at 75° C. is added a solution of KMnO4 (1.5 g, 9.49 mmol) in water (200 mL) slowly. After the addition is complete, the reaction mixture is stirred at 75° C. for another 1 hour. Solid KOH is added to make the solution alkaline and the mixture is filtered while it is hot. To the filtrate is added EtOH (10 mL) and EtOAc (50 mL). The organic phase is separated and discarded. The aqueous phase is acidified with concentrated HCl to pH 5 and extracted with EtOAc (60 mL) and DCM (60 mL). The organic phases are combined, dried, and concentrated to give the title product (1.9 g, 88.46%yield). MS (m/z): 233.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.ON1C2C=CC=CC=2N=N1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:19][O:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)(=[O:11])=[O:10])[CH2:17][CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (138 mg, 0.72 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (195 mg, 0.60 mmol), 1-hydroxybenzotriazole (97.0 mg, 0.72 mmol), 4-chlorobenzoic acid (94.0 mg, 0.60 mmol) and N,N-diisopropylethylamine (233 mg, 1.80 mmol) in N,N-dimethylformamide (6 ml). The reaction mixture was stirred at room temperature for 17 hours and quenched with H2O (8 ml) and aqueous 1 N HCl solution (pH=3). The aqueous phase was extracted with CH2Cl2 (20 ml×3) and the combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 67/33) to give 4-chloro-N-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)benzamide (172 mg, 62%) as a white solid: LCMS: 463 [M+1]+. 1H NMR (DMSO-d6) δ: 1.70 (m, 2H), 1.90 (m, 2H), 3.01 (m, 2H), 3.13 (m, 2H), 3.98 (d, 1H), 7.51 (d, 2H), 7.68 (m, 2H), 7.95 (m, 2H), 8.11 (m, 2H), 11.6 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:10]=2)[N:5]=[CH:4][NH:3]1.Cl>CCOC(C)=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]([OH:15])=[O:14])[CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: CC(C)(C)OC(=O)Cc1ccc2nc[nH]c(=O)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc2nc[nH]c(=O)c2c1

Procedure:
A solution of tert-butyl 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetate (0.25 g, 0.96 mmol) in 10 mL of satd.HCl in EtOAc was stirred at rt for 4 hours. The mixture was concentrated in vacuo at rt, and the residue was used in the next reaction without further purification. MS (ESI, pos. ion) m/z: 205.1 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[O:16][CH2:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[O:20][CH:21]([CH3:27])[C:22]([O:24]CC)=[O:23].[OH-].[Na+].Cl>CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[O:16][CH2:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[O:20][CH:21]([CH3:27])[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)C(C)Oc1ccccc1COc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ccccc1COc1cccc(OCc2ccc3ccccc3n2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2.65 mmol) of the ester from step C in 25 ml of EtOH is added 10 ml (10.0 mmol, 3.75 equiv) of 1N NaOH. The mixture is stirred for 1 hour at room temperature which time the mixture is acidified to pH~4 using 1N HCl. A precipitate forms which is filtered off and recrystallized from hot MeOH-Et2O to afford 2-(2-(3-((quinolin-2-yl)methyloxy)phenoxymethyl)phenoxy)propionic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=3)[CH:26]=2)(=[O:31])=[O:32])[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
In dichloromethane (18 ml), 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine (517 mg) and 6-chloro-2-naphthylsulfonyl chloride (588 mg) were dissolved under ice cooling. To the resulting solution, diisopropylethylamine (0.59 ml) was added, followed by stirring at room temperature for 63 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby the title compound (688 mg, 71%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH:15]=[CH2:16])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]>C1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH2:15][CH3:16])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=Cc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.4 %

Procedure:
6-Hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester (1.27 g, 5.11 mmol) was dissolved in benzene (10 mL) and EtOAc (10 mL). Tristriphenylphosphine rhodium chloride (150 mg) was added and the reaction was placed under an atmosphere of hydrogen. Stirring at room temperature was continued. After 14 hours, the solvents were removed in vacuo and the crude material was purified by silica gel chromatography to provide 1.14 g (88%) of the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ=1.19 (t, J=7.8 Hz, 3H), 2.10 (s, 3H), 2.60 (q, J=7.8 Hz, 2H), 3.89 (s, 6H), 6.87 (s, 1H), 10.79 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.CO[CH:17](OC)[CH2:18][C:19](=O)[CH3:20]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:17][CH:18]=[C:19]([CH3:20])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: COC(CC(C)=O)OC
Solvent: CC(=O)O
Product: Cc1ccnc2nc(SCc3ccccc3)nn12
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A solution of 50 g (0.24 mol) of 3-amino-5-benzylthio-1,2,4-triazole in 500 ml of glacial acetic acid was added dropwise over 3-4 hours to a solution of 34.0 g (0.25 mol) of acetylacetaldehyde dimethyl acetal in 500 ml of glacial acetic acid heated at 100° C. After the addition was complete the reaction mixture was heated at reflux overnight, cooled to room temperature and poured into an ice-water mixture. The solid which separated was collected by filtration and recrystallized from ethanol to yield 27 g (41%) of the desired product as a solid, m.p. 102°-104° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C[O-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH3:28])[C:15]([OH:27])=[C:16]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=O)[CH:17]=1.C(O)C>CO>[Cl:11][C:12]1[CH:13]=[C:14]([CH3:28])[C:15]([OH:27])=[C:16]([C:18](=[N:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH:17]=1
Reactant: NCCCC(=O)O
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Cc1cc(Cl)cc(C(=NCCCC(=O)O)c2ccc(Cl)cc2)c1O

Procedure:
4-Aminobutanoic acid (2.2 g; 0.0213 mol), sodium methoxide (1.16 g; 0.0213 mol) and (5-chloro-2-hydroxy-3-methylphenyl)-(4-chlorophenyl)-methanone (6 g; 0.0213 mol) are introduced into a mixture of 200 ml of ethanol and 400 ml of methanol, and the resulting mixture is then evaporated to dryness. Ethanol (500 ml) is added to the residue and the mixture is then evaporated to dryness. The latter operation is repeated 4 times. The residue is dissolved in 1 liter of water and the pH is acidified to pH 4 by the addition of citric acid. The precipitate is filtered off, washed with water and then dissolved in CH2Cl2. The organic solution is washed with water, dried (MgSO4) and filtered, and the filtrate is evaporated to give an oil, which is crystallised once from petroleum ether and recrystallised twice from AcOEt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6]([F:17])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([O:15][CH3:16])[CH:11]=[CH:10]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:30][C:31]#[N:32]>C1COCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:5]1[C:6]([F:17])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([O:15][CH3:16])[CH:11]=[CH:10]2)[CH2:30][C:31]#[N:32]
Reactant: COC(=O)Cc1c(F)ccc2ccc(OC)nc12
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1c(F)ccc2ccc(OC)nc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of (7-fluoro-2-methoxy-quinolin-8-yl)-acetic acid methyl ester (1.0 g, 4.0 mmol; prepared as in WO 2007/081597) in THF (10 mL) cooled to −78° C. was added LiHMDS (1M, 4.43 mL, 1.2 eq.) dropwise over 15 min. The resulting orange mixture was stirred at −78° C. for 2 h. Bromoacetonitrile (1.5 eq.) was added dropwise over 20 min and stirring was continued at −78° C. for an additional 2 h. The reaction was quenched with water and extracted with EA (3×). The combined org. phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by CC (Hept/EA 2:1 to 1:1) to afford the title intermediate as a colourless solid (953 mg, 82% yield). MS (ESI, m/z): 289.4 [M+H+].
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: C#CCCCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
To an ice-cold solution of 11-hydroxyundecyne (10 g, 59.4 mmoles) in 400 ml of methylene chloride under argon was added in one portion carbon tetrabromide (40.5 g, 0.1224 mole). The reaction mixture was stirred at 0° C. for 5 minutes and triphenylphosphine (29.43 g, 0.1122 mole) was added. The reaction was kept at 0° C. for an additional 15 minutes and stirred at room temperature for 3 hours. The methylene chloride was removed in vacuo. The residue was treated with hexane and the combined organic extract was concentrated in vacuo. The crude product was purified by flash chromatography on silica, eluting with straight hexane, to give 7.2 g (52%) of 11-bromoundecyne as a colorless oil. Following the procedures of Examples 20 and 39(a), a mixture of salicylaldehyde, 11-bromoundecyne and potassium carbonate in dimethylformamide is reacted to furnish 2-(10-undecynyloxy)benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][C:26]([C:31](O)=[O:32])=[CH:25][C:24]2=[O:34]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:26]1[O:27][C:28]2[C:23]([C:24](=[O:34])[CH:25]=1)=[CH:22][C:21]([Cl:20])=[CH:30][CH:29]=2)=[O:32]
Reactant: O=C(O)c1cc(=O)c2cc(Cl)ccc2o1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cc(=O)c2cc(Cl)ccc2o1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-chloro-4-oxo-4H-chromene-2-carboxylic acid. MS: 466.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:15]([CH2:16][CH3:17])=[C:14]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)[C:13]([CH2:27][CH3:28])=[C:12]([CH2:29][NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[N:32]=3)[C:11]=2[CH2:38][CH3:39])[CH:5]=[CH:4][CH:3]=1.CO[CH:42](OC)[CH2:43][C:44](=O)[CH3:45].OP(O)(O)=O>O>[CH3:42][C:43]1[N:37]=[C:33]2[C:34]([CH:35]=[CH:36][C:31]([NH:30][CH2:29][C:12]3[C:13]([CH2:27][CH3:28])=[C:14]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]5[C:22](=[N:26][C:4]([CH3:5])=[CH:3][CH:2]=5)[N:21]=4)[C:15]([CH2:16][CH3:17])=[C:10]([CH2:9][NH:8][C:6]4[CH:5]=[CH:4][C:3]5[C:2](=[N:1][C:11]([CH3:12])=[CH:10][CH:9]=5)[N:7]=4)[C:11]=3[CH2:38][CH3:39])=[N:32]2)=[CH:45][CH:44]=1
Reactant: CCc1c(CNc2cccc(N)n2)c(CC)c(CNc2cccc(N)n2)c(CC)c1CNc1cccc(N)n1
Reactant: COC(CC(C)=O)OC
Agent: O=P(O)(O)O
Solvent: O
Product: CCc1c(CNc2ccc3ccc(C)nc3n2)c(CC)c(CNc2ccc3ccc(C)nc3n2)c(CC)c1CNc1ccc2ccc(C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
1,3,5-Tris[(6-amino-pyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene (2b) (4.7 g, 8.9 mmol), 4,4-dimethoxy-2-butanone (26.3 mmol), and H3PO4 (50 mL) were held at 90° for 4 h and then stirred at room temperature for 2 h. The reaction mixture was poured into water (300 mL), neutralized, and extracted several times with chloroform. The collected organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified several times by column chromatography (silica gel, CHCl3/CH3OH, 7:1 to 2:1 v/v). Yield 23%. M.p. 207-208° C. 1H-NMR (400 MHz, CDCl3): δ=1.23 (t, 9H, J=7.5 Hz), 2.69 (s, 9H), 2.82 (q, 6H, J=7.5 Hz), 4.74 (br s, 3H), 4.82 (d, 3H, J=3.0 Hz), 6.58 (d, 3H, J=8.6 Hz), 7.04 (d, 3H, J=8.1 Hz), 7.72 (d, 3H, J=8.6 Hz), 7.79 (d, 3H, J=8.1 Hz). 13C NMR (100 MHz, CDCl3): δ=16.9, 23.1, 25.3, 40.6, 112.1, 115.2, 118.3, 132.9, 136.2, 136.9, 144.5, 156.7, 158.4, 161.3. HR-MS calcd for C42H44N6: 674.3719; found: 674.3714. Rf=0.89 (CHCl3/CH3OH 2:1 v/v).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][C:11](Cl)=[O:12].Cl.[CH3:15][NH:16][O:17][CH3:18]>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:11](=[O:12])[CH2:10][O:9][CH3:8]
Reactant: CNOC
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
35.96 ml of triethylamine (258 mmol), followed by a solution of 14 g of methoxyacetyl chloride (Aldrich, 129 mmol) in 250 ml of dichloromethane, are added to a solution of N-methyl-O-methylhydroxylamine hydrochloride in 250 ml of dichloromethane cooled to 0° C. The mixture is stirred for 3 hours while allowing it to return to ambient temperature. A 1N solution of HClaq is added and then the organic phase is washed with water, dried over sodium sulphate, filtered, and concentrated under vacuum. 13.14 g of expected product are obtained in the form of an oil which is used without subsequent purification (crude yield=76%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][OH:22])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: N[C@H]1CC[C@H](CO)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CO)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.21 g, 0.98 mmol) (Example 1, Step 2), (trans-4-aminocyclohexyl)methanol (from J&W Pharmatech, 0.25 g, 2.0 mmol) and N,N-diisopropylethylamine (0.51 mL, 2.9 mmol) in isopropyl alcohol (3.3 mL) was heated at 90° C. for 2 h. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 60% EtOAc in hexanes) to give the desired product (0.26 g, 86%). LCMS calculated for C14H18N3O3S (M+H)+: m/z=308.1. Found: 308.0.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CS(O[CH2:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)=O.[Na+].[I-]>>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:22][CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Product: Clc1ccc(CN2CCC(CNCCC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 54 %

Procedure:
4-(Aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) was alkylated with 3,3-diphenylpropyl methanesulfonate (1.0 equiv.) in the presence of NaI (2.6 equiv.) in CH2CN at 70° C. for 16 h. General workup and column chromatography (SiO2) afforded 1-(4-chlorobenzyl)-4-{N-(3,3-diphenylpropyl)aminomethyl}piperidine (118 mg, 54%): The purity was determined by RPLC (98%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[CH:15]=[CH2:16]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (7.05 g, 21.33 mmol, prepared as described in Epp et al., WO 2013003740 A1) and vinyltri-n-butyltin (7.52 mL, 25.6 mmol) were suspended in 1,2-dichloroethane (71.1 mL) and the mixture was degassed with Argon for 10 min. Bis(triphenylphosphine)palladium(II) chloride (1.497 g, 2.133 mmol) was then added and the reaction mixture was stirred at 70° C. overnight (clear orange solution). The reaction was monitored by gas chromatography-mass spectrometry (GC-MS). After 20 h, the reaction mixture was concentrated, adsorbed onto Celite, and purified by column chromatography (SiO2; hexanes/ethyl acetate gradient) to afford the title compound as a light brown solid (3.23 g, 65.7%): mp 99-100° C.; 1H NMR (400 MHz, CDCl3) δ 6.87 (dd, J=18.1, 11.6 Hz, 1H), 5.72 (dd, J=11.5, 1.3 Hz, 1H), 5.52 (dd, J=18.2, 1.3 Hz, 1H), 4.79 (s, 2H), 3.91 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −138.79 (s); EIMS m/z 230.