Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[H][H]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: [H][H]
Reactant: COCCOc1ccc(C=CC(=O)O)cc1OCCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCOc1ccc(CCC(=O)O)cc1OCCOC
Yield: 74.5 %

Procedure:
To a solution of 3-[3,4-Bis-(2-methoxy-ethoxy)-phenyl]-acrylic acid (20 g, 67.5 mmol) in EtOAc (100 ml) and MeOH (100 ml) was added carefully 10% Pd/C (1.5 g), then the mixture was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen. The solution was passed through a celite pad, and the filtrate was concentrated to give product (15 g, 78.5%). LC-MS: m/e 297 (M−1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH2:10])=O)[CH:5]=[C:4]([CH3:11])[N:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:10])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C(N)=O)cc(Cl)n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C#N)cc(Cl)n1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To a mixture of 2-chloro-6-methylpyridine-4-carboxamide (5.1 g, 30 mmol) obtained above, pyridine (7.3 mL, 90 mmol) and tetrahydrofuran (50 mL) was added dropwise a solution of trifluoroacetic anhydride (6.4 mL, 45 mmol) in tetrahydrofuran (10 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 0.5 hr and at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→10/90). The obtained solution was concentrated under reduced pressure to give the title compound (4.3 g, 95%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:7][CH:8]1[C:17]2[CH:16]=[C:15]([OH:18])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH:9]1[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.Br[CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].O>CCCCCC.CC(N(C)C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:7][CH:8]1[C:17]2[CH:16]=[C:15]([O:18][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH:9]1[N:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Reaction time: 48 h
Yield: 96.5 %

Procedure:
NaH in paraffin (0.278 g, 6.38 mmol, 55% in paraffin) was washed with n-hexane and suspended in DMA (30 ml). 8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (1.2 g, 3.19 mmol) in DMA (20 ml) was added. After stirring for 1 h at room temperature tert-butyl 2-bromoethylcarbamate (2.14 g, 6.38 mmol) was added in portions and the mixture was stirred for 48 h. Water was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, and concentrated to afford a residue that was purified by flash chromatography (silica gel, MeOH/CH2Cl23:97). The product (1.6 g, 97%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:33][CH3:34])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:28][CH:27]([C:29]([O:31]C)=[O:30])[CH2:26]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:33][CH3:34])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:26][CH:27]([C:29]([OH:31])=[O:30])[CH2:28]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To a solution of methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D90) (120 mg) in isopropanol (40 mL) and water (10 mL) stirred under nitrogen at room temperature was added a solution of NaOH (9.62 mg) in water in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid (E41) (12 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.07 (3H, t), 1.34 (6H, d), 2.70 (2H, m), 2.87 (2H, m), 3.59 (3H, m), 4.29 (4H, m), 4.79 (1H, m), 7.30 (4H, m), 7.82 (1H, s), 7.87 (1H, dd), 7.99 (1H, d), 10.06 (1H, br s), 13.15 (1H, br s). δF (DMSO-d6, 376 MHz): −73.6. MS (ES): C26H29ClN2O3S requires 484. found 485.2 (M+H+).
Reaction SMILES: BrC1[C:7]([NH2:8])=[C:6](Br)[N:5]=[C:4]([C:10]#[N:11])[CH:3]=1.[CH3:12]B1OB(C)OB(C)O1.O1[CH2:26][CH2:25]OCC1>O.C(=O)([O-])[O-].[K+].[K+]>[NH2:11][C:10]1[C:25]([CH3:26])=[CH:12][C:6]([C:7]#[N:8])=[N:5][C:4]=1[CH3:3]
Reactant: N#Cc1cc(Br)c(N)c(Br)n1
Reactant: CB1OB(C)OB(C)O1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C#N)nc(C)c1N

Procedure:
4,6-dibromo-5-amino-2-cyanopyridine (1 g) was dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). Trimethylboroxin (1.3 g), Pd(dppf)Cl2-DCM complex (264 mg) and potassium carbonate (1.5 mg) were added to the solution, and the mixture was reacted using a microwave reactor at 140° C. for four hours. The reaction mixture was returned to mom temperature and then partitioned by adding ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 100%) to give the title compound (390 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH-].[NH4+:15].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:15])(=[O:12])=[O:11]
Reactant: COc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a solution of 2-chloro-5-methoxybenzenesulfonyl chloride (2.5 g, 10.4 mmol) (i.e. the product of Step A) in tetrahydrofuran (30 mL) was added 30% ammonium hydroxide (3.0 mL, 25.7 mmol) dropwise. The reaction mixture was stirred for 15 minutes, during which time a suspension formed. To this mixture water (10 mL) was added, and the tetrahydrofuran was evaporated under reduced pressure to leave an aqueous suspension of a tan solid. The solid was isolated by filtration and washed with water to afford 2.2 g of the title compound. 1H NMR (CDCl3) δ 7.63 (d, 1H), 7.43 (d, 1H), 7.03 (d, 1H), 5.13 (br s, 2H), 3.85 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30]O)=[CH:29][C:24]=2[O:23][CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][N:15]3[CH2:16][C:17](=[O:18])[N:13]([C:11]4[CH:10]=[N:9][N:8]([CH2:7][C:6]5[C:2]([CH3:1])=[N:3][O:4][C:5]=5[CH3:20])[CH:12]=4)[C:14]3=[O:19])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccc4c(c3)OCO4)C2=O)cn1
Yield: 19 %

Procedure:
Prepared as in example 10-35 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and benzo[d][1,3]dioxol-5-ylmethanol. Yield: 19%. 1H NMR (DMSO, 400 MHz): δ2.143 (s, 3H), 2.408 (s, 3H), 3.977 (s, 2H), 4.440 (s, 2H), 5.202 (s, 2H), 6.003 (s, 2H), 6.897 (m, 3H), 7.788 (s, 1H), 8.181 (s, 1H). MS M+H calculated 410.1; found 410.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.07 uM.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=C[CH:14]=1.[O:19]1[CH2:23]C[CH2:21][CH2:20]1>>[ClH:1].[C:6](=[O:12])([O:7][CH2:8][CH2:18][NH:13][CH3:14])[O:5][CH2:2][CH2:23][O:19][CH2:20][CH3:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccncc1
Reactant: C1CCOC1
Product: CCOCCOC(=O)OCCNC
Product: Cl

Procedure:
To a solution (20 mL) of bis(trichloromethyl)carbonate (0.43 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.35 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 10 min., 2-ethoxyethyl 2-(methylamino)ethyl carbonate hydrochloride (0.82 g) obtained in Reference Example 48 was added. A solution (1 mL) of triethylamine (0.60 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 3 days. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0.63 mL) and 4-dimethylaminopyridine (0.037 g) were added, and the mixture was stirred at 60° C. for 6 hrs. and at room temperature for 11 hrs. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate:hexane=7:3) to give the title compound (1.39 g) as a yellow amorphous solid.
Reaction SMILES: [C:1]12([CH2:11][NH:12][CH2:13][CH2:14][CH:15]([OH:17])[CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(CC)CC.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]12([CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([CH3:16])[O:17][C:26]3=[O:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(O)CCNCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCN(CC23CC4CC(CC(C4)C2)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of 4-(1-adamantylmethylamino)butan-2-ol (50 mg, 0.21 mmol) and Et3N (42.4 mg, 0.42 mmol) in CH2Cl2 (5 mL) at 0° C. under N2, a solution of triphosgene (25 mg, 0.084 mmol) in CH2Cl2 (1 mL) was added dropwise. The mixture was stirred at rt for 1 h. The mixture was concentrated to give crude product, which was purified by preparative TLC to afford 3-((1-adamantyl)methyl)-6-methyl-1,3-oxazinan-2-one (12 mg, 21%). 1H NMR (CD3OD, 400 MHZ): δ=1.46 (d, 3H), 1.72˜2.18 (m, 17H), 3.02 (d, 1H), 3.34 (d, 1H), 3.44 (m, 1H), 3.63 (m, 1H), 4.58 (m, 1H); MS m/z=264
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:13][C@H:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH3:15]>>[Cl:1][C:2]1[C:3]([C:4]([NH:13][C@H:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH3:15])=[O:6])=[CH:7][C:8]([F:11])=[CH:9][N:10]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 45 from 2-chloro-5-fluoronicotinic acid and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.9 Hz), 8.05 (2H, d, J=8.4 Hz), 7.92 (1H, dd, J=7.8, 2.9 Hz), 7.47 (2H, d, J=8.4 Hz), 6.91 (1H, m), 5.36 (1H, m), 3.92 (3H, s), 1.64 (3H, d, J=6.9 Hz).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=[O:3])[CH3:2].[I-].[K+].C(N(CC)CC)C.Cl[CH2:36][C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38]>CN(C=O)C.O>[C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:36][C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)C(=O)COC(=O)c1cccc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-benzoic acid (compound of Example 68-(b)-[1]) (0.72 g) and potassium iodide (0.37 g) are dissolved in DMF, and thereto are added triethylamine (0.2 g) and 2-chloro-N,N-diethylacetamide (0.33 g) with stirring at room temperature, and the mixture is reacted three nights. The reaction mixture is mixed with water and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography using silica gel (eluant, chloroform). The fractions containing the desired compound are collected, and chloroform is distilled off under reduced pressure to give the title compound (0.71 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([CH3:12])=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](Cl)=[O:9].[H-].[Na+].[CH2:15]([O:17][C:18](=[O:28])[CH:19]=[CH:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:16].O>O1CCCC1>[CH2:15]([O:17][C:18](=[O:28])[C:19]([C:8]([C:7]1[CH:6]=[N:5][C:4]([CH3:12])=[C:3]([CH3:2])[CH:11]=1)=[O:9])=[CH:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:16]
Reactant: Cc1cc(C(=O)Cl)cnc1C
Reactant: CCOC(=O)C=CNc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)c1cnc(C)c(C)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 7.7 %

Procedure:
3.31 g (16.0 mmol) of 5,6-dimethyl-nicotinoyl chloride hydrochloride 6a (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351) was dissolved in 35 mL of dry tetrahydrofuran and cooled down to −10° C. under nitrogen atmosphere. To the resultant solution was added 1.60 g (40.0 mmol) of 60% sodium hydride and the mixture was stirred for 15 minutes, followed by the addition of 3.06 g (16.0 mmol) of 3-phenylamino-acrylic acid ethyl ester 5a. The mixture was stirred at −10° C. for 2 hours, followed by the addition of 100 mL of water to the reaction mixture. The product was extracted twice with 100 mL dichloromethane. The combined organic extracts were dried with MgSO4 and concentrated in vacuo. Purification of the crude product using flash chromatography (10-75% ethyl acetate in hexane) yielded 400 mg of 2-(5,6-dimethyl-pyridine-3-carbonyl)-3-phenylamino-acrylic acid ethyl ester 2d as a yellow solid.
Reaction SMILES: [S:1]([Cl:5])([Cl:4])(=[O:3])=[O:2].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>C(#N)C>[ClH:4].[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:9][CH2:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1CCNCC1
Solvent: CC#N
Product: CN1CCN(S(=O)(=O)Cl)CC1
Product: Cl

Procedure:
Sulfuryl dichloride (1.22 ml, 15.0 mmol) was added at room temperature to a solution of N-methylpiperazine (0.555 ml, 5.00 mmol) in acetonitrile (10 ml) and the whole was stirred under reflux for 6 hours. The reaction mixture was concentrated in vacuo and the resulting solid was collected and washed with diethyl ether to give 4-methylpiperazine-1-sulfonyl chloride hydrochloride.
Reaction SMILES: [CH3:1]OCC(O)=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:43]([N:50]([CH2:56][CH:57]1[CH2:59][CH:58]1OC)[C:51](=O)[CH2:52][O:53][CH3:54])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.B.C1COCC1>ClCCl.C1COCC1>[CH2:43]([N:50]([CH2:56][CH:57]1[CH2:59][CH:58]1[CH3:1])[CH2:51][CH2:52][O:53][CH3:54])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COCC(=O)N(Cc1ccccc1)CC1CC1OC
Reactant: COCC(=O)O
Agent: B
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCN(Cc1ccccc1)CC1CC1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Coupling In a 500 mL flask methoxyacetic acid (2.24 g, 24.8 mmol), N-benzyl-1-(2-trans-methylcyclopropyl)methanamine hydrochloride (5.0 g, 23.6 mmol) and DIPEA (13.4 g, 104 mmol) were dissolved in 300 mL of dichloromethane. To this solution at rt BOP (11.0 g, 24.8 mmol) was added as a solid portionwise and stirred 15 minutes. The reaction mixture was evaporated ini vacuo. Purification by flash chromatography (25-35% ethyl acetate:hexanes) provided a mixture of cis and trans amides as a clear oil: ES MS (M+H)=248.1. Step B: Reduction A 500 mL flask charged with N-benzyl-2-methoxy-N-(2-methoxycyclopropyl)methyl acetamide (from step A, 7.75 g, 31.3 mmol) in THF (100 mL) was added BH3-THF (1.0 M, 94 mL, 94 mmol) dropwise via an addition funnel. Upon complete addition (10 min.) the mixture was refluxed for 14 h. The mixture was allowed to cool to rt and quenched carefully with MeOH (15 mL). The mixture was then treated with 15 mL concentrated HCl and heated to reflux for 5 h. The reaction was evaporated in vacuo and partitioned between ethyl acetate and 20% NaOH solution. The aqueous layer was washed with ethyl acetate (3×). The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo. Purification by reverse phase LC gave N-benzyl-2-methoxy-N-(2-methylcyclopropyl)methylethanamine as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 5H), 3.70 (bq, J=13.5 Hz, 2H), 3.49 (bs, 2H), 3.31 (s, 3H), 2.75 (bm, 2H), 2.51 (m, 1H), 2.31 (m, 1H), 1.03 (d, J=5.86, 3H), 0.59 (m, 1H), 0.48 (m, 1H), 0.22 (m, 2H). ES MS (M+H)=234.2. Step C: Hydrogenation A degassed solution of N-benzyl-2-methoxy-N-(2-methylcyclopropyl)methylethanamine (4.89 g, 20.9 mmol) in 150 mL ethyl alcohol was treated with palladium hydroxide (20% on carbon, 0.29 g) and hydrogen chloride (5.24 mL of a 4M solution in dioxane, 21 mmol) then placed under a hydrogen atmosphere for 16 hours. The reaction mixture was degassed with nitrogen, filtered through celite, washed with methanol and evaporated in vacuo to give (2-methoxyethyl)[(2-methylcyclopropyl)methyl]amine hydrochloride as a pale yellow oil: 1H NMR (400 MHz, CD3OD) δ 3.65 (m, 2H), 3.41 (s, 3H), 3.21 (m, 2H), 2.92 (m, 2H), 1.09 (d, J=5.68 Hz, 3H), 0.80 (m, 2H), 0.57 (m, 1H), 0.46 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:34])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:61][C:62]([F:73])([F:72])[C:63]1[CH:68]=[CH:67][C:66](B(O)O)=[CH:65][CH:64]=1>>[CH3:33][S:30]([N:27]1[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:11]4[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=4)=[C:2]([C:66]4[CH:67]=[CH:68][C:63]([C:62]([F:73])([F:72])[F:61])=[CH:64][CH:65]=4)[C:3]3=[O:34])=[CH:8][CH:7]=2)[CH2:29][CH2:28]1)(=[O:31])=[O:32]
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(C(F)(F)F)cc2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2ccc(C(F)(F)F)cc2)=C3c2ccc(C(F)(F)F)cc2)CC1
Yield: 21 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-6-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]-3-[4-(trifluoromethyl)phenyl]-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, and 4-(trifluoromethyl)phenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (21%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:28]=[C:27]([CH:34]=O)[CH:26]=2)=[CH:21][CH:20]=1>>[C:30]([N:29]1[C:25]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:26][C:27]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[N:28]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Product: Cc1cccc(N2CCN(CCNCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)c1C
Yield: 77.8 %

Procedure:
Compound 22 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6].[NH:23]1C=CN=[CH:24]1>>[N:2]1([CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:6])[CH:1]=[CH:24][N:23]=[CH:22]1
Reactant: CN(C)CCC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Reactant: c1c[nH]cn1
Product: O=C(CCn1ccnc1)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
3-(Dimethylamino)-1-(2-phenyl-1H-indol-3-yl)-1-propanone was converted to the methiodide (36 g) which was then reacted with imidazole (34 g) to give a solid which was crystallised from methanol, to give the title compound (15.40 g), m.p. 206°-208°; λmax (EtOH) 255 nm (ε19,650), λmax 307.5 nm (ε12,840), identical with the material obtained in Example 3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[Br:17]N1C(=O)CCC1=O>COCCOCCOC>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[Br:17])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)C(Br)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.9 g of ethyl p-cyanophenylacetate in 50 ml of diglyme is added to a slurry of 0.48 g of sodium hydride (50% oil dispersion) in 10 ml of diglyme. The reaction mixture is stirred at room temperature for 2 h, cooled to 0° and 1.75 g of N-bromosuccinimide is added portionwise. The solvent is evaporated under high vacuum and the residue is chromatographed on 50 g of silica with ether to yield ethyl-α-bromo-p-cyanophenylacetate.