Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>O>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of toluene (70 mL) and water (10 mL) was degassed with nitrogen for 30 min. A mixture of sodium carbonate (3.2 g, 30.43 mmol), 4-bromobenzaldehyde (2.0 g, 10.6 mmol), 4-trifluoromethoxyphenylboronic acid (2.86 g, 13.95 mmol) and tetrakis triphenyl phosphene palladium(0) (1.0 g, 1.562 mmol) were added to the above degassed water/toluene mixture. The reaction mixture refluxed overnight. After the reaction is completed, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ (ppm)=7.2-8.0 (m, 8H), 10.0 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[N:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OC)(OC)OC>[CH3:20][O:17][C:16](=[O:18])[CH2:15][C:13]1[N:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[S:11][CH:12]=1
Reactant: CC(C)c1ccc(-c2nc(CC(=O)O)cs2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)Cc1csc(-c2ccc(C(C)C)cc2)n1
Yield: 884.2 %

Procedure:
A solution of 6.9 g (26.4 mmol) of [2-(4-isopropyl-phenyl)-thiazol-4-yl]-acetic acid and 0.5 g of p-toluenesulfonic acid mono-hydrate (catalyst) in 70 ml of methanol and 5 ml of trimethyl orthoformate was heated at reflux for 5 hours. After neutralization with aqueous sodium bicarbonate solution, evaporation of the solvents, extraction of the residue with tert-butyl methyl ether, drying over anhydrous sodium sulfate and evaporation of the solvent, 6.4 g (88% of theory) of [2-(4-isopropyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester were obtained as light brown oil.
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH3:16])[N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.[Cu]I>[CH3:25][O:24][C:21]1[N:22]=[CH:23][C:18]([NH:17][C:2]2[C:3]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH3:16])[N:9]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:19][CH:20]=1
Reactant: CSc1nc(C)nc(-c2nccnc2F)n1
Reactant: COc1ccc(N)cn1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(Nc2nccnc2-c2nc(C)nc(SC)n2)cn1
Temperature: 100 °C
Yield: 76.3 %

Procedure:
A glass microwave reaction vessel was charged with 2-(3-fluoropyrazin-2-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (61 mg, 0.257 mmol), 5-amino-2-methoxypyridine (0.038 mL, 0.309 mmol), copper(I) iodide (5 mg, 0.026 mmol) and N,N-diisopropylethylamine (0.089 mL, 0.514 mmol) in dioxane (1 mL). The reaction mixture was stirred and heated at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 20% EtOAc/CH2Cl2 to give N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrazin-2-amine (67 mg, 0.196 mmol, 76% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.34 (s, 1H); 8.36 (d, J=1.90 Hz, 1H); 8.26 (s, 2H); 8.00 (dd, J=8.99, 2.56 Hz, 1H); 6.80 (d, J=8.77 Hz, 1H); 3.96 (s, 3H); 2.77 (s, 3H); 2.68 (s, 3H). m/z (ESI, +ve ion) 342.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:24]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NCc4ccccc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (100 mg) was dissolved in methanol (1 ml), and benzaldehyde (39 mg), zinc chloride (49 mg) and sodium cyanoborohydride (23 mg) were added. The mixture was stirred at room temperature for 2 hr and refluxed under heating for 15 min. Benzaldehyde (16 mg), zinc chloride (21 mg) and sodium cyanoborohydride (10 mg) were added and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added ice water, and then a saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. Hexane was added to the residue and the precipitated pale-yellow crystals were washed, collected by filtration and dried under reduced pressure to give the objective compound (120 mg).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].C(N(C(C)C)CC)(C)C.[NH:54]1[CH2:59][CH2:58][CH:57]([CH2:60][C:61]([O:63]CC)=[O:62])[CH2:56][CH2:55]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([N:54]3[CH2:55][CH2:56][CH:57]([CH2:60][C:61]([OH:63])=[O:62])[CH2:58][CH2:59]3)=[O:35])=[O:30])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CCOC(=O)CC1CCNCC1
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: O
Solvent: CN(C)C=O
Product: O=C(O)CC1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a mixture of 20 mg of 3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)-benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoic acid 4.1e, 28 mg of diisopropylethylamine, and 6.5 mg of ethyl 2-(piperidin-4-yl)acetate in 1 mL of DMF was added 17 mg of HATU. The mixture was stirred at 60° C. for 1 h. The solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, then brine. It was dried and the solvent was evaporated at reduced pressure. It was dissolved in 4:1 methanol/water and treated with 19.4 mg of LiOH.H2O. After stirring for 20 h the product was isolated by reverse phase HPLC, eluting with 0.5% TFA in a gradient of water and acetonitrile to give 10.9 mg of product. MS (ES, m/z): 728.7 [M+H]+.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[CH2:2]1.[Br:14]N1C(=O)CCC1=O.O.CC(C)=O.CCOCC>CN(C=O)C>[Br:14][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][CH2:2][N:3]3[C:4](=[O:13])[CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2cccc3c2N1CC3
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=C1CCc2cc(Br)cc3c2N1CC3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (10.0 g, 55.8 mmol) in 100 ml dry DMF was added dropwise a solution of N-bromosuccinimide (10.4 g, 58.6 mmol) in 150 ml dry DMF at 0° C. The mixture was stirred at 0° C. for 2 h, then 400 ml water was added and the solution was extracted with ethyl acetate (3×150 ml). The organic phase was washed with water (2×200 mL), then dried over MgSO4 and evaporated, affording a yellow solid, which was purified by crystallization from acetone/ether providing pure 8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]-quinolin-4-one (12.8 g, 50.8 mmol, 91%) as pale yellow needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N-:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[C:4]([N+:22]([O-])=O)[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[NH2:22][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1
Reactant: COc1cc(C[N-]c2ccc(F)cc2[N+](=O)[O-])cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cc(CNc2ccc(F)cc2N)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(4-Fluoro-2-nitrophenyl) 3,4,5-trimethoxybenzylamide (17.1 mmol, 6.0 g) in absolute ether (100 ml) is added to LiAlH4 (63.4 mmol, 2.4 g) in absolute ether (40 ml) and the mixture is stirred at room temperature for 16 hours. While cooling with an ice bath, the suspension is quenched with water (40 ml) and is extracted with ether (3×100 ml). The combined organic layers are dried with MgSO4, filtered and evaporated. Flash-chromatography (hexane:ethylacetate 1:1) and subsequent recrystallisation from ethanol yield the title product.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C@@H:6]1[C@H:11]2[CH2:12][CH2:13][N:8]([CH2:9][C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:2].C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.C(=O)(O)[O-]>C(O)C>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]([C@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([CH2:9][C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:16]
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C(=O)C2
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Agent: O=C([O-])O
Solvent: CCO
Product: CCN(CC)C(=O)[C@@H]1CN2CC[C@@H]1C(=O)C2
Reaction time: 8 h
Yield: 40.5 %

Procedure:
(3R*,4R*)-N,N-Diethyl-5-oxo-1-azabicyclo[2.2.2]octane-3-carboxamide (180 g, 0.804 mol) and (-)-dibenzoyl-L-tartaric acid (L-DBT) monohydrate (211 g, 0.561 mol) were added to ethanol (3.65 L), and the resultant mixture was heated at reflux until a clear solution was obtained. The solution was rapidly cooled down to c.a. 40° C. in a water-bath, and allowed to stand overnight to form crystals, which were collected by filtration. The obtained crystals (100.5 g, 21.5%) were found to be (+)-(3R,4R)-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2]-octane-3-carboxamide L-DBT salt with 97% optical purity. An additional amount of (-)-L-DBT monohydrate (90.6 g, 0.241 mol) was added to the mother liquor, which was concentrated to c.a. 3.5 L by evaporation. The resulting mixture was heated at reflux to give a clear solution, which was allowed to stand at room temperature. After 2 days, formed crystals were collected by filtration. The crystals (117 g, 25%) were found to be (-)-(3S,4S)-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2]-octane-3-carboxamide L-DBT salt with 92% optical purity. The same resolution process was repeated starting from 220 g of (3R*,4R*)-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2]-octane-3-carboxamide. From this run, the L-DBT salt of the (+) enantiomer (180 g, 31%) with 95% optical purity and the L-DBT salt of the (-) enantiomer (91 g, 16%) with 97% optical purity were obtained. The L-DBT salt of the (-) enantiomer from the above two runs were combined, and suspended in 1.5 l of ethanol. The resulting suspension was heated at reflux for 3 hours, and allowed to stand overnight at room temperature. The obtained crystals were converted to the free amine by base treatment (aqueous bicarbonate) followed by extraction with methylene chloride to afford (-)-(3S,4S)-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2]-octane-3-carboxamide (73 g, 18%) having greater than 99% optical purity. Similarly, 83 g of of the (+) enantiomer (21%) was obtained with greater than 99% optical purity. The above mentioned optical purities were determined using a chiral HPLC. The absolute configuration was determined by X-ray crystallography of the dibenzoyl-L-tartaric acid salt of the (-) enantiomer.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[C:14]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:23]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[N:24]S(C(C)(C)C)=O)#[N:15].Cl>C(OCC)C>[Br:13][C:9]1[CH:8]=[C:7]([C:23]2([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:17]3[C:16](=[C:21]([F:22])[CH:20]=[CH:19][CH:18]=3)[C:14]([NH2:15])=[N:24]2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc(C(=NS(=O)C(C)(C)C)c2cccc(F)c2C#N)ccn1
Reactant: Brc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
n-Butyllithium (1.7 mL, 4.17 mmol) (2.5 M in hexanes) was dropwise added to 1,3-dibromobenzene (0.504 mL, 4.17 mmol) in diethyl ether (25.00 mL) at −78° C. under argon. The resulting mixture was stirred at −78° C. for 1 h. Additional n-butyllithium (2.5 M in hexanes) (0.8 mL, 2.00 mmol) was added and the resulting reaction mixture was stirred at −78° C. for 30 min. N-((2-Cyano-3-fluorophenyl)(2-methoxypyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.500 g, 4.17 mmol) in diethyl ether (10.00 mL) was added dropwise and stirring was continued for 1 h at −78° C. Hydrochloric acid (25.04 mL, 12.52 mmol) (0.5 M in methanol) was added and the resulting reaction mixture was stirred at room temperature over night and concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica chromatography using 0% to 5% (3.5 M ammonia in methanol) in dichloromethane gave the title compound 0.812 g, (47% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]1([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[OH:9])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: Oc1ccc(F)cc1-c1ccccc1
Temperature: 50 °C
Yield: 98.3 %

Procedure:
After adding 2-bromo-4-fluorophenol (4.16 g, 20.32 mmol, Aldrich) into a flask, nitrogen flow is allowed into the flask. Then, palladium acetate (0.22 g, 1.02 mmol), potassium phosphate (21.00 g, 91.19 mmol), phenylboronic acid (2.97 g, 24.36 mmol), triphenylphosphine (0.80 g, 3.06 mmol) were added into the flask. Dimethoxyethane (32 ml) and distilled water (8 ml) were added thereto and stirred thoroughly. The mixture was heated to 50° C. and stirred for 6 hours. When the reaction is over, the mixture was allowed to cool at a room temperature, and then the organic layer was separated from the mixture by using diethylether (10 ml×3) and water. After adding magnesium sulfate to the separated organic layer, it was stirred for 30 minutes. The mixture was filtered and volatile materials of the mixture were then removed. The residue was added in a dried flask and dissolved in methylenechloride. After decreasing the temperature up to −78° C., boron tribromide (30.48 ml of 1.0M solution in methylenechloride, Aldrich) was slowly dropped thereon. When the dropped boron tribromide settled down, it was then allowed to react for 1 hour, and the temperature of the mixture was raised at a room temperature, and then stirred for 12 hours. An organic layer was separated from the obtained product by using diethylether (10 ml×3) and water, and then the organic layer was stirred for 30 minutes with added magnesium sulfate. After filtration, the volatile materials were removed, and then the resulting product was purified through a chromatography column packed with silica gel using hexane and methylchloride (1.5:1) as mobile phase. Then, after removing the volatiles, 3.76 g of white solid was obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:26])[C:21](=[O:27])[CH2:20][CH2:19]4)[CH:13]=[N:14][CH:15]=2)[CH2:5][CH2:4]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:26][N:22]1[C:23]2[C:18](=[CH:17][C:16]([C:12]3[CH:11]=[C:10]([O:9][C@H:6]4[CH2:5][CH2:4][C@H:3]([NH:2][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:8][CH2:7]4)[CH:15]=[N:14][CH:13]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20][C:21]1=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CC[C@H](N)CC4)c3)ccc21
Agent: Cl
Product: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CC[C@H](NS(C)(=O)=O)CC4)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 38, 6-[5-((trans)-4-amino-cyclohexyloxy)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 71) and methanesulfonyl chloride gave the title compound as a light yellow amorphous solid. MS: 430.4 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2(O)[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C1(C)C(C)=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(N(CC)CC)C>O.C(OCC)(=O)C>[CH2:16]([N:12]1[CH2:13][CH2:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1cccc(C2=CCCN(Cc3ccccc3)C2)c1
Temperature: 140 °C
Yield: 72.4 %

Procedure:
A mixture of 3.25 g of the product of Step A and 65 ml of xylene was heated to 140° C. with stirring and after the addition of 2 g of phosphoric acid anhydride, the mixture was stirred at 140° C. for 2 hours and was then iced. Ice was then added to the mixture with caution and was diluted with water and ethyl acetate. The mixture was made alkaline by addition of triethylamine and was stirred until total dissolution occurred. The mixture was filtered and the decanted aqueous phase was extracted with ethyl acetate. The organic extract was washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 1.97 g of 1-benzyl-3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [CH2:1]([NH:8]/[CH:9]=[CH:10]/[C:11](=[O:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(N(CC)CC)C.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37])([O-:29])=[O:28]>CC(O)C.O>[CH2:1]([N:8]([CH2:9][CH2:10][CH:11]([OH:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[S:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N+:27]([O-:29])=[O:28])(=[O:37])=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)C(=O)/C=C/NCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(OC)C(O)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 7 h
Yield: 89.6 %

Procedure:
To a solution of (E)-4-(benzylamino)-1,1-dimethoxybut-3-en-2-one (1.176 g, 5 mmol) in a mixture of 2-Propanol (12.5 ml) and Water (1.200 ml) was added sodium borohydride (0.757 g, 20.00 mmol) in portions, the mixture was stirred for 7 hours. Quenched with 5N HCl to pH 7 (approx 2.5 ml), pH adjusted to 8-9 with 5N NaOH, diluted with MTBE (25 ml) and brine (15 ml). Organic phase was separated, triethylamine (0.767 ml, 5.50 mmol) was added with ice-cooling followed by 2-nitrobenzene-1-sulfonyl chloride (1.108 g, 5.00 mmol). The mixture was left at 0-5° C. (fridge) overnight. Washed with water, dried, evaporated to dryness, the residue applied on a column, eluted with petroleum ether-ethyl acetate mixture 1:1, fractions collected to give N-benzyl-N-(3-hydroxy-4,4-dimethoxybutyl)-2-nitrobenzenesulfonamide (1.9 g, 4.48 mmol, 90% yield), yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[C:12]=2[O:15][CH3:16])[CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:7][C:8]2[C:13](=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[C:9]=2[O:21][CH3:22])[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCCCCC1(C(=O)OCC)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(CCCCCCCC(=O)O)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Reaction time: 6 h
Yield: 22.7 %

Procedure:
A mixture comprised of an ethanol (8 ml) solution of ethyl 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoate (367 mg, 0.764 mmols) and an aqueous sodium hydroxide solution (1N, 0.764 ml, 0.764 mmols) was stirred at room temperature for 6 hours, and an aqueous sodium hydroxide solution (1 N, 0.153 ml, 0.153 mmols) was added thereto and the stirring was continued at room temperature for further 6 hours. The reaction mixture was concentrated in vacuo, which was made acidic by adding 1 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:2) to obtain the entitled compound (78.6 mg) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([C:11]1[CH:30]=[CH:29][C:14]([CH2:15][O:16][C:17]([N:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:21][CH3:22])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH:31]([C@@H:33]1[C@@H:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:36][N:35]([C@H:44]([CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)[C:45]([O:47]CC2C=CC(OC)=CC=2)=[O:46])[CH2:34]1)=O>>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]([N:19]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:33]3[C@@H:37]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:36][N:35]([C@H:44]([CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]4)[C:45]([OH:47])=[O:46])[CH2:34]3)[CH2:25][CH2:24]2)[CH2:20][CH2:21][CH3:22])=[O:18])=[CH:29][CH:30]=1)([O-:10])=[O:9]
Reactant: CCCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 86.3 %

Procedure:
The title compound was prepared from 4-(N-((4-nitrobenzyl)oxycarbonyl)-N-(prop-1-yl)amino)-piperidine trifluoroacetate (21 mg, 0.048 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (14 mg, 0.028 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 15 mg (89%) of the title compound. ESI-MS: 621.4 (M+H); HPLC A: 2.61 min.