Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][CH2:14]CO)=[N:8][C:7]([CH3:17])=[C:6]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:24][O:25][CH2:26][CH2:27]CN>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][CH2:14][CH2:27][CH2:26][O:25][CH3:24])=[N:8][C:7]([CH3:17])=[C:6]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2c(NCCO)nc(C)c(-c3ccccc3)c2c1
Reactant: COCCCN
Product: COCCCNc1nc(C)c(-c2ccccc2)c2cc(OC)ccc12

Procedure:
Following the procedure for 2-[(6-methoxy-3-methyl-4-phenylisoquinolin-1-yl)amino]ethanol, using (in Step B) 3-methoxy-1-aminopropane in place of ethanolamine, the titled compound was synthesized.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13](=[O:18])NCOC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13](=[O:18])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCNC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-3-(Methoxymethylcarbamoyl)pyrrolidine-1-carboxylic acid t-butyl ester (400 mg, 1.6 mmol) and THF (10 mL, 0.1 mol) were combined under nitrogen. The solution was cooled at 0° C. using an ice bath. 1.0 M of Phenylmagnesium bromide in THF (7.0 mL, 7.0 mmol) was added dropwise over 5 minutes. The mixture was slowly warmed to room temperature and stirred for 30 minutes. The mixture was cooled in an ice bath and the reaction was quenched by the slow addition of water (15 mL). The mixture was extracted with EtOAc (1×100 mL), and the organic layer was washed with sat. NaCl (50 mL), dried over Na2SO4, filtered, and concentrated to yield 849 mg of crude product, which was purified by flash chromatography (12 g column, 20-100% EtOAc in hexanes over 17 minutes), and placed under high vacuum for 15 minutes to yield 372 mg of the title compound as a clear oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>Cl.[Rh]>[NH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCc1ccc2ncccc2c1
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Product: CCOC(=O)CCc1ccc2c(c1)CCCN2
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A stirred mixture of ethyl 3-(6-quinolinyl)propanoate (0.3 g, Reference Example 3) in hydrochloric acid (3 ml, 0.1N) and 5% rhodium in carbon powder (33 mg) was hydrogenated in a 22 cm3 stainless steel pressure reactor at a pressure of 50 bars of hydrogen. After stirring for 4 hours at 25° C. a further portion of 30 mg of 5% rhodium in carbon powder (33 mg) was added and the hydrogenation was continued under a pressure of 50 bars at 25° C. for 1 hour. The reaction mixture was filtered through a pad of celite and the filter pad was washed with hydrochloric acid (3 ml, 0.1N) then with ethyl acetate (25 ml). The combined filtrate and washings were combined and the aqueous phase was decanted from the organic phase. The aqueous phase was extracted twice with ethyl acetate (25 ml) and combined with the aforementioned organic phase. The combined solutions were dried over magnesium sulfate then evaporated under reduced pressure (2.0 kPa) at 40° C. to give the title compound (0.121 g) as a brown oil.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:10][N:9]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[C@H:8]([CH2:24][O:25][CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCOCC1.[Pd]>[C:1]([O:5][C@H:6]1[CH2:10][N:9]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:7]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@@H]1C[C@@H](COC/C=C/c2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)O[C@@H]1C[C@@H](COCCCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Yield: 93.5 %

Procedure:
Hydrogenation: A solution of (E)-(2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-2-(3-phenyl-allyloxymethyl)-pyrrolidine (2.3 g) in ethanol/dioxane 1:2 (75 ml) was hydrogenated in the presence of 10% palladium on charcoal (0.50 g) at 1.1 bar and room temperature for 4 h. The reaction mixture was filtered over a pad of celite and washed with ethanol. The filtrate was concentrated, and the residue was chromatographed on silica gel using EtOAc/hexane 1:4 as eluent to obtain (2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-2-(3-phenyl-propoxymethyl)-pyrrolidine (2.16 g) as a gum, MS: 482 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[C@H:9]1[C:14](=[O:16])[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[F:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 20 h

Procedure:
To a solution of (2R,3S)-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (120 mg, 0.514 mmol) in CH2Cl2 (5 mL) were added successively 3-chloro-2-fluorobenzylamine (0.065 mL, 0.514 mmol), HBTU (293 mg, 0.772 mmol) and DIPEA (0.18 mL, 1.03 mmol), and stirring was continued at RT for 20 h. The reaction mixture was then diluted with CH2Cl2, and the organics were washed with 0.1N aqueous HCl (2×), aqueous NaHCO3 (2×) and brine (1×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 1:4 to 1:3) to afford the title compound as a white foam. TLC Rf (EtOAc/c-hexane 1:1)=0.62; MS (LC/MS): 397 [M+Na]+, 319 [MH−tBu]+, 275 [MH−Boc]+; tR (HPLC conditions b): 4.72 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3cccnc3)C2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3cccnc3)C2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine (0.45 g, 1.16 mmol) in dichloromethane (6 mL). Cool in an ice bath. Add methanesulfonyl chloride (0.015 mL, 1.15 mmol) and triethylamine (0.032 mL, 1.6 mmol). After 1 hour, dilute the reaction mixture with dichloromethane and extract with brine. Separate the layers and extract the aqueous layers twice with dichloromethane. Combine the organic layers. Dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[C:34](O)=[O:35])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[C:34]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:35])=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: COc1ccc(-c2ocnc2C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)cc1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS (basic): tR=1.31 min; [M+H]+=476.1.
Reaction SMILES: [CH:1]([C:4]1[C:13]([CH:14]([CH3:16])[CH3:15])=[N:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[OH2:17]>C(O)(=O)C>[CH:1]([C:4]1[C:13]([CH:14]([CH3:16])[CH3:15])=[N:12][C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:17])[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)c1nc2c(nc1C(C)C)CCCC2
Solvent: CC(=O)O
Product: CC(C)c1nc2c(nc1C(C)C)C(=O)CCC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.5 g of 5,6,7,8-tetrahydro-2,3-diisopropylquinoxaline was dissolved in 10 ml of acetic acid, followed by the dropwise addition of a solution of 1.0 g of chromic acid anhydride in acetic acid (6 ml) /water (1 ml). The obtained mixture was stirred at 80° C. for 2 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 10% ethyl acetate/hexane) to give 0.6 g of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:21][CH2:22][OH:23]>O>[CH2:1]([N:3]([CH2:21][CH2:22][OH:23])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccc(Br)cc1
Reactant: OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCN(CCO)c1ccc(Br)cc1
Temperature: 125 °C
Yield: 69.5 %

Procedure:
17.3 g (86.7 mmols) of N-ethyl-4-bromoaniline, 22.7 ml (1.5-fold equivalent weight) of N,N-diisopropylethylamine and 9.64 ml (1.5-fold equivalent weight) of 2-bromoethanol were mixed, and the mixture obtained was heated at 125° C. for 2 hours in an atmosphere of argon. Next, to the reaction solution obtained, 1.5 ml (0.1-fold equivalent weight) of diisopropylethylamine and 0.64 ml (0.1-fold equivalent weight) of 2-bromoethanol were added, and the mixture obtained was heated at 125° C. for 3 hours in an atmosphere of argon. Water was added to the reaction solution obtained, which was then extracted with ethyl acetate. The organic layer obtained was dried with anhydrous magnesium sulfate and then concentrated. The residue thus obtained was purified by silica gel column chromatography developing system (chloroform) to obtain 14.7 g of N-ethyl-N-(2-hydroxyethyl)-4-bromoaniline (yield: 69.5%; a colorless oily liquid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)[CH3:20].O>CN(C)C=O>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[C:5]([C:11]#[N:12])=[CH:6]2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: N#Cc1c[nH]c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(Br)ccc32)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
To a solution of 5-bromo-3-cyanoindole (2.0 g) in N,N-dimethylformamide (50 mL) were added cesium carbonate (7.4 g) and 4-fluorobenzoic acid ethyl ester (3.0 g), and this mixture was stirred at 80° C. for 48 hours. This reaction mixture was poured into water, and the precipitated solid was collected by filtration. This solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (1.8 g).
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1.P(OCC)(OCC)OCC.O>CN(C)C=O>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C:3]2[NH:2][C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:5]([CH3:13])[N:4]=2)[CH:19]=[CH:18][C:17]=1[S:20][CH3:21]
Reactant: COc1cc(-c2nc(C)c(-c3cccnc3)n2O)ccc1SC
Agent: CCOP(OCC)OCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(C)c(-c3cccnc3)[nH]2)ccc1SC
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a solution of 1-hydroxy-2-(3-methoxy-4-methylthiophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.98 g) in N,N-dimethylformamide (10 ml) was added triethyl phosphite (1.03 ml), and the mixture was stirred at 90° C. for 3 hours. Then the solution was poured into water (60 ml) and stirred at ambient temperature for an hour. The resulting precipitates were filtered, washed with water, and recrystallized from ethanol (6 ml) to give 2-(3-methoxy-4-methylthiophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.58 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]1[CH:17]2[CH:12]([CH2:13][NH:14][CH2:15][CH2:16]2)[CH2:11][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH2:1]([N:14]1[CH2:15][CH2:16][CH:17]2[CH2:9][N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][CH:12]2[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCNCC2C1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CCN(Cc3ccccc3)CC2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
0.777 g of benzylbromide (4.54 mmol) were added dropwise to a mixture of 1.028 g of commercially available tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (4.54 mmol), 1.883 g potassium carbonate (13.62 mmol) and a spatula tip of 18-crown-6 in 25 ml of tetrahydrofurane. The reaction mixture was stirred for 16 h at room temperature, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane, the organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated to yield 1.413 g of product that was used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15].[C:16]([N:23]1[CH2:31][CH2:30][CH2:29][C@@H:25]([C:26](O)=[O:27])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)=[O:27])=[C:3]([NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: COCCCNc1cc(C#N)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNc1cc(C#N)ccc1NC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
4-Amino-3-(3-methoxypropylamino)benzonitrile (41B) (3.50 mmol, 718 mg) in DMF (25 mL) was added (R)-(−)—N-Boc-Nipecotic acid (4.55 mmol, 1.04 g) and N-methylmotpholine (10.50 mmol, 1.15 mL). The reaction mixture was stirred at rt for 5 min and then added HATU (5.25 mmol, 2.00 g) and kept stirring at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, NaHCO3, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel EtOAc-hexane: 1:2) to afford (R)-tert-butyl 3-(4-cyano-2-(3-methoxypropylamino)phenylcarbamoyl)piperidine-1-carboxylate (41C) (2.40 mmol, 1.01 g, three-step yield: 68.6%). ESI-MS: m/z 417.5 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][O:17][C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1)(=[O:13])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(CCc1ccccc1)NCCO
Reactant: Clc1cccc2nccn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(CCc1ccccc1)NCCOc1cccc2nccn12
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.20 g, 5 mmoles) in dimethylformamide (20 ml) was added 2-(N-benzylmethylsulfonylamino)-1-ethanol (1.14 g, 5 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (0.763 g, 5 mmoles) with stirring under ice-cooling, followed by stirring at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, which was extracted with ethyl acetate and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)] to obtain 0.68 g of the desired product (39.4%, pale yellow oily product).
Reaction SMILES: [NH:1]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=3[C:2]1=2.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O.O>[C:19]1([CH2:18][N:1]2[C:10](=[O:11])[CH2:9][CH2:8][C:7]3[N:6]=[CH:5][C:4]4[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=4[C:2]2=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2ncc3ccccc3c2N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2ncc3ccccc3c2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
A stirred solution of 1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one (3.97 g) in dimethylsulfoxide (sieve dried, 80 ml) was treated sequentially with powdered potassium hydroxide (2.64 g of 85% KOH) and benzyl bromide (3.76 g). The solution was stirred for 1.5 hours at ambient temperature, transferred to a separatory funnel, diluted with water (400 ml) and extracted with ethyl acetate (2×250 ml). The organic phase was washed with water (2×200 ml), dried (Na2SO4), filtered and evaporated to give a solid (4.9 g). Recrystallization from 95% ethanol (32 ml) gave 3.35 g of crystals, m.p. 153.5°-155.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[N:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:49]2[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccncc2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (90.0 mg, 0.132 mmol), pyridine-4-boronic acid (81.0 mg, 0.659 mmol), Pd(PPh)3Cl2 (4.60 mg, 0.0065 mmol), 2 M Na2CO3 (aq., 0.198 mL, 0.396 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (40 min gradient of 0-80% CH3CN in 0.05% aqueous formic acid) yielded the product (15.6 mg, 17%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[CH2:15][C:16](N)=[O:17])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:20][Mg]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[CH3:20])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C[Mg]Br
Reactant: CC(CC(N)=O)c1ccc(C2CCCCC2)c(Cl)c1
Product: CC(=O)CC(C)c1ccc(C2CCCCC2)c(Cl)c1
Yield: 74 %

Procedure:
4-(3-Chloro-4-cyclohexyl-phenyl)-2-pentanone was prepared analogous to Example 61 from 3-(3-chloro-4-cyclohexyl-phenyl)-butyramide and methyl-magnesium bromide with a yield of 74% of theory. The colorless, highly viscous oil had a b.p. of 153°-156°C at 0.1 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](Cl)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12].Cl>O1CCOCC1>[NH:1]([C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=C(Cl)Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of aniline (18.4 mL, 202 mmol) in TEA (28.2 mL, 202 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (22.9 g, 67.4 mmol) in dioxane (220 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was treated with 10% HCl and extracted with Et2O (3×). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc gave 3,3-dianilino-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one as an off-white solid (13.10 g, 43%): 1H-NMR (d6-DMSO, 300 MHz) δ12.24 (br s, 1H), 9.20 (br s, 1H), 7.95 (s, 1H), 7.12–7.42 (m, 10H), 4.82 (s, 1H); Rf=0.60 (6:1 Hex:EtOAc).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=2)=[O:28])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: COc1c(C)cn2ccccc12
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n2ccccc12
Yield: 89.8 %

Procedure:
1.8 ml (12.92 mmol) of triethylamine are added, at ambient temperature under an inert atmosphere, to 1.7 g (10.77 mmol) of 1-methoxy-2-methylindolizine in 15 ml of dichloroethane, followed, dropwise, by 2.2 g (11.85 mmol) of 4-nitrobenzoic acid chloride. The reaction medium is stirred for 30 minutes at ambient temperature, hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is washed with diethyl ether. 3 g of an orange solid are obtained.