Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1.C([Li])CCC.CCCCCC.[CH:23](OCC)=[O:24].Cl>C(OCC)(=O)C.O1CCCC1>[S:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH:23]=[O:24])=[CH:3][C:4]=2[S:9][CH2:8][CH2:7]1
Reactant: Brc1ccc2c(c1)SCCS2
Reactant: CCOC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)SCCS2
Reaction time: 0.5 h

Procedure:
To 5 mL of a tetrahydrofuran solution containing 500 mg of 6-bromo-2,3-dihydro-1,4-benzodithiin, 0.67 mL of a 2.67 mol/L butyllithium/hexane was added at −78° C., the mixture was stirred for 0.5 hour, then 300 mg of ethyl formate was added thereto, and the mixture was further stirred for 2 hours. Thereto was added 1 mol/L hydrochloric acid, and ethyl acetate was then added to the mixture. The organic layer was separated, washed with an aqueous saturated sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60N manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate:hexane 1:4] to obtain 121 mg of a brown oily substance, 2,3-dihydro-1,4-benzodithiin-6-carbaldehyde.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][CH:6]=1.[NH3:17]>CO>[F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH2:17])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cc1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc(OCC(F)(F)F)cc1

Procedure:
A solution of methyl 4-(2,2,2-trifluoroethoxy)-benzoate (3 g., 0.013 mole) in methanol (25 ml.) is cooled using a dry-ice acetone bath, and the solution is saturated with anhydrous ammonia, then heated in a pressure reactor at 110° for 10 hours. The methanolic solution is filtered and the filtrate is evaporated. The residue is chromatographed on neutral alumina and the early fractions which elute rapidly with ethyl acetate are discarded, methyl ethyl ketone fractions are discarded and methanol fractions finally give a tan solid when evaporated. When recrystallized from ethanol the white solid is found to be 4-(2,2,2-trifluoroethoxy)benzamide, m.p. 177°-178° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C.Cl>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([B:27]([OH:28])[OH:26])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(CCOCc2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(CCOCc2ccccc2)cc1
Reaction time: 3 h
Yield: 71 %

Procedure:
13.7 g (47.1 mmol) of 4-(2-benzyloxyethyl) phenylbromide and 80 ml of dry THF were cooled to -75° C., and 34.0 ml of n-butyllithium (1.65M) was dripped to it. Stirring at the foregoing temperature was performed for 3 hours, and then mixture solution of 12.9 g (68.7 mmol) of triisopropoxyboron and 50 ml of dry THF was dripped, and stirring at -75° C. was performed for 2 hours and that at room temperature was performed for 14 hours. After the reactions had been completed, 50 ml of 10% hydrochloric acid was added, and extraction with ethyl acetate was performed. After the extracted solution was dried, the solvent was removed by filtration. Then, refining was performed with a silica gel column chromatography (developing solvent: toluene/ethyl acetate=20/1) so that 8.62 g of 4-(2-benzyloxyethyl) phenyl boronic acid was obtained (yield 71%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH-].[K+].[F:13][C:14]([F:19])([F:18])[CH:15]([OH:17])[CH3:16].Cl>CS(C)=O>[F:13][C:14]([F:19])([F:18])[CH:15]([O:17][C:2]1[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=1)[CH3:16]
Reactant: CC(O)C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(Oc1ccc(C(=O)O)cn1)C(F)(F)F
Reaction time: 8 h
Yield: 70.7 %

Procedure:
6-Chloronicotinic acid (0.500 g, 3.17 mmol), powdered potassium hydroxide (0.712 g, 12.69 mmol) and 1,1,1-trifluoropropan-2-ol (0.724 g, 6.35 mmol) were combined in DMSO (12 mL) and heated in a sealed tube to 100 C for 18 h. The mixture was acidified to pH 1 by adding 2M hydrochloric acid. The mixture was then left to stand at room temperature overnight and the resultant precipitate filtered off, washed with water and dried under vacuum to afford the title compound as a cream solid (0.527 g, 71%). 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.82 (1H, d), 8.29 (1H, dd), 6.94 (1H, d), 5.96 (1H, m) and 1.52 (3H, d).
Reaction SMILES: [OH-].[K+].[CH3:3][NH:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].C(O)[CH2:18][OH:19]>>[OH:19][CH2:18][CH2:12][O:11][C:9]1[CH:10]=[C:5]([NH:4][CH3:3])[C:6]([N+:14]([O-:16])=[O:15])=[CH:7][C:8]=1[OH:13]
Reactant: OCCO
Reactant: CNc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [K+]
Agent: [OH-]
Product: CNc1cc(OCCO)c(O)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
0.06 mol (3.9 g) of 85% pure potassium hydroxide pellets is dissolved in 60 ml of ethylene glycol on a boiling water bath. 0.03 mol (5.9 g) of 2-methylamino-4,5-methylenedioxy-1-nitrobenzene, prepared according to Example 3, is added with stirring in the course of 5 minutes.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][C@@H:9]3[C@@H:14]([CH2:15][C:6]=2[S:5][C:4]=1[N:31](C)[C:32](=O)OC(C)(C)C)[N:13]([CH3:16])[CH2:12][C@H:11]([C:17]([N:19]([C:23](=[O:30])[NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH2:20][CH2:21][CH3:22])=[O:18])[CH2:10]3)#[N:2].C(OCC)(=O)C.[ClH:46]>C(OCC)(=O)C>[ClH:46].[ClH:46].[C:1]([C:3]1[C:7]2[CH2:8][C@@H:9]3[C@@H:14]([CH2:15][C:6]=2[S:5][C:4]=1[NH:31][CH3:32])[N:13]([CH3:16])[CH2:12][C@H:11]([C:17]([N:19]([CH2:20][CH2:21][CH3:22])[C:23]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[O:30])=[O:18])[CH2:10]3)#[N:2]
Reactant: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(NC)c3C#N)C[C@H]2N(C)C1
Temperature: 25 °C

Procedure:
To a mixture of tert-butyl N-[(4aR*,6R*,8aR*)-3-cyano-6-[({[2-(dimethylamino)ethyl]carbamoyl}(propyl)amino)carbonyl]-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-2-yl]-N-methylcarbamate (160 mg) and ethyl acetate (10 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) while stirring at room temperature, and the mixture was stirred at the same temperature for 11 hours. To the reaction mixture was added a 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) while stirring at room temperature, and then stirred at the same temperature for 13 hours. The solid was collected by filtration to give the title compound (compound 3-1) (116 mg). The structure was illustrated in Table 11.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[CH3:28][NH:29][C@@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>ClC(Cl)C.O1CCCC1>[OH:36][C@@H:33]1[CH2:34][CH2:35][C@H:30]([N:29]([CH3:28])[C:8]([NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)=[O:27])[CH2:31][CH2:32]1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CN[C@H]1CC[C@@H](O)CC1
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N(C)[C@H]3CC[C@@H](O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with cis-4-Methylamino-cyclohexanol in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=3[F:35])[C:21]([O:23]C)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=3[F:35])[C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COC(=O)C(Oc1ccc2c(N)nccc2c1)c1cc(OC)c(OC)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(F)c(C(Oc2ccc3c(N)nccc3c2)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
7C (80 mg, 0.21 mmol) was dissolved in THF (2 mL). 1M LiOH (0.4 mL) was added, and the reaction was stirred at rt for 0.5 h. Additional 1M LiOH was added (0.4 mL) and the reaction was stirred for 3 h. The solvent was removed under reduced pressure, and water (10 mL) was added. The solution was acidified with 1 N HCl, then purified via preparative HPLC (MeOH/water/TFA) to provide 7D (65 mg, 64%). LC-MS: 373.18 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][NH:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CNC(=O)COc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a stirred solution of Intermediate 19 (0.84 g) in tetrahydrofuran (30 ml) at 0° C. was added lithium aluminium hydride (0.64 g). The reaction was stirred at room temperature for 3 h, followed by reflux for 2 h. On cooling water (0.64 ml), aqueous sodium hydroxide (15%, 0.64 ml) and water (1.9 ml) were added. The precipitates were removed by filtration and the filtrate diluted with ethyl acetate (30 ml) and extracted with aqueous hydrochloric acid (2M, 2×30 ml). The aqueous layer was basified to pH 12 with aqueous sodium hydroxide (2M), and extracted with methanol/dichloromethane (10%, 2×50 ml). The combined organic extracts were washed with brine (40 ml) dried over magnesium sulphate (2 g) and the solvent removed in vacuo to yield the title compound as a pale yellow oil (0.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (64) (40 mg, 0.21 mmol) using Method D. The residue was triturated with TBME (3 ml) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[C:22]3[N:29]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[CH:28]=[CH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:32][CH2:31][CH2:30][N:29]1[C:22]2[C:21]([NH:20][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:18])([F:19])[F:17])[CH:10]=4)=[C:2]([CH3:1])[CH:3]=3)=[N:26][CH:25]=[N:24][C:23]=2[CH:27]=[CH:28]1
Reactant: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ncnc3ccn(CCN)c23)ccc1Oc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
tert-Butyl {2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (523 mg) was dissolved in dichloromethane (6.4 mL), trifluoroacetic acid (4.8 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), and washed with aqueous sodium hydrogen carbonate (40 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (420 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([F:18])([F:17])[C:4]([C:7]([C:9]([F:16])([F:15])[C:10]([F:14])([F:13])[O:11][CH3:12])=[O:8])([F:6])[F:5].Cl[CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+]>CCOCC>[CH3:12][O:11][C:10]([F:13])([F:14])[C:9]([F:15])([F:16])[C:7]1([C:4]([F:6])([F:5])[C:3]([F:17])([F:18])[O:2][CH3:1])[O:22][CH2:21][CH2:20][O:8]1
Reactant: OCCCl
Reactant: COC(F)(F)C(F)(F)C(=O)C(F)(F)C(F)(F)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(F)(F)C(F)(F)C1(C(F)(F)C(F)(F)OC)OCCO1
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of 58 g (about 0.2 mol) of crude bis(2-methoxytetrafluoroethyl) ketone, 16.9 g (0.21 mol) of 2-chloroethanol, and 50 mL of ether was stirred while 29.0 g (0.21 mol) of anhydrous K2CO3 were added in portions with cooling. The resulting reaction mixture was stirred overnight, filtered and distilled to give 40.7 g of 2,2-bis(2-methoxytetrafluoroethyl)-1,3-dioxolane, b.p. 81° at 40 Pa (0.3 mm), m.p. 39°-40°. Dissolution of the resulting filter cake in water, filtration of the resulting mixture and drying gave another 8.5 g of product, m.p. 38.5°-40°, for a total yield of 49.2 g (74%). IR (CCl4) and NMR (CCl4) of the product were consistent with the assigned structure. Anal.: Calcd. for C9H10F8O4 : C, 32.35; H, 3.02; F, 45.48. Found: C, 32.14; H, 3.19; F, 45.22.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:41])(=[O:40])[CH2:30][C:31]([CH2:36][C:37]([OH:39])=[O:38])([C:33]([OH:35])=[O:34])[OH:32]>CC(O)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:41])(=[O:40])[CH2:30][C:31]([CH2:36][C:37]([O-:39])=[O:38])([C:33]([O-:35])=[O:34])[OH:32]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Sitagliptin base (150 mg) was suspended in 2-propanol (2.5 mL). Citric acid (71 mg) was added and the mixture was stirred for one hour at ambient temperature and 2 hours at 40° C. The mixture was allowed to cool to ambient temperature and stirred for 24 hours at this temperature. The solid was filtered and dried at ambient temperature.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]#[N:31])[CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[C:30]([CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:25]1)#[N:31]
Reactant: N#CC1CCCNC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCCC(C#N)C3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and piperidine-3-carbonitrile (33 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 35-60% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a orange solid (52 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H) 1.73-2.11 (m, 4H) 3.25-3.34 (m, 1H) 3.53-3.63 (m, 1H) 3.68-3.79 (m, 1H) 3.98 (dd, J=12.51, 2.65 Hz, 1H) 4.12-4.23 (m, 1H) 6.38 (d, J=2.27 Hz, 1H) 7.46 (s, 1H) 7.60 (d, J=8.59 Hz, 2H) 8.00 (d, J=8.59 Hz, 2H) 8.12 (d, J=2.27 Hz, 1H) 10.93 (s, 1H). ESI-MS: m/z 405.3 (M+H)+.
Reaction SMILES: B.C1COCC1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=4)[C:18](=[O:29])[CH:17]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.CCN(CC)CC.CO>C1COCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=4)[C@@H:18]([OH:29])[CH:17]=3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CCCOc1ccc2c(c1)C(=O)C=C2c1ccc2c(c1)OCO2
Agent: B
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCOc1ccc2c(c1)[C@@H](O)C=C2c1ccc2c(c1)OCO2
Temperature: -10 °C

Procedure:
A 100 ml three-necked flask was charged with anhydrous THF (20 mL), (R) -MeCBS catalyst (0.325 mL, 1 M, 0.325 mmol), and BH3-THF (6.49 mL, 1M, 6.49 mmol) under nitrogen. The solution was cooled to −10° C. and 3-(1,3-benzodioxol-5yl)-6-propoxy-1H-inden-1-one (2.0 g, 6.49 mmol) in anhydrous THF (20 mL) was added dropwise over 2 h period. After 45 minutes a solution of Et3N (2.0 mL, 14.3 mmol) and MeOH (1.3 mL, 19.5 mmol) was added cautiously while maintaining the internal temperature below −5° C. The reaction mixture was concentrated in vacuo and purified via flash chromatography (EtOAc/hexane, 1:3) affording (S)-3-(1,3-benzodioxol-5-yl)-6-propoxy-1H-inden-1-ol as a yellow oil (1.9 g, 95%, 94% e.e.); Chiralcel OC column (90:10 IPA/hexane, 2 mL/min, 254 nm): 13.321 min (2.34%) :16.031 min (85.23%); 1H NMR (CDCl3) δ7.30 (d, J=8.3 Hz, 1H), 7.2 (s, 1H), 7.1-7.0 (m, 2H), 6.9 (d, J=8.0 Hz, 1H), 6.8 (dd, J=8.4, 2.4 Hz, 1H), 6.25 H), 6.0 (s, 2H), 5.2 (d, J=7.2 Hz, 1H), 3.95 (t, J=6.6 Hz, 3H), 1.85 (m, 2H), 1.0 (t, J=, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13]CC)=O)[CH:2]=1.[H-].[K+]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](=[O:13])[CH2:7][CH2:6][CH:5]2[CH2:4][CH2:3][CH2:2][NH:1][CH2:10]2)[CH:2]=1
Reactant: CCOC(=O)c1cnc2ccccc2c1
Agent: [H-]
Agent: [K+]
Product: O=C(CCC1CCCNC1)c1cnc2ccccc2c1
Yield: 100 %

Procedure:
The operation is as in Example 1, but starting from 4.5 g of ethyl quinoline-3-carboxylate, 6 g of ethyl 3-[3-(N-benzoyl)piperidyl]propionate and 13 ml of a 20% suspension of potassium hydride in oil. 3 g of crude 1-(3-quinolyl)-3-(3-piperidyl)-1-propanone are obtained.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-octenyl)pyridine (Example 33) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.14 (m, 4 H), 4.33 (d, J=5.5 Hz, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.23 (sept, J=6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.25 (m, 3 H), 1.15 (m, 10 H), 0.87 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C26H38FNO) 399, found 400 (M+H). Anal. Calcd for C26H38FNO: C, 78.15; H, 9.59; N, 3.51. Found: C, 78.27; H, 9.81; N, 3.43. Gummy oil; Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:51][C:52]1[C:57]([F:58])=[C:56]([F:59])[CH:55]=[CH:54][C:53]=1B(O)O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:11][C:7]1[CH:6]=[C:3]([CH:4]=[O:5])[C:2]([C:55]2[CH:54]=[CH:53][C:52]([F:51])=[C:57]([F:58])[C:56]=2[F:59])=[CH:9][C:8]=1[CH3:10])[CH3:13]
Reactant: CCOc1cc(C=O)c(Br)cc1C
Reactant: OB(O)c1ccc(F)c(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CCOc1cc(C=O)c(-c2ccc(F)c(F)c2F)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
To a degassed solution of 2-bromo-5-ethoxy-4-methylbenzaldehyde (300 mg, 1.31 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (53.8 mg, 0.131 mmol; S-Phos ligand) palladium (II) acetate (14.7 mg, 0.065 mmol) in THF (8 mL) were added K3PO4 (834 mg, 3.93 mmol) and (2,3,4-trifluorophenyl)boronic acid (276, 1.57 mmol). The reaction mixture was stirred at 70° C. under a N2 atmosphere for 16 hours, cooled to room temperature and filtered and the filtrate was concentrated by evaporation under reduced pressure. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to provide the title intermediate (255 mg) as white solid.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33]([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CN(C=O)C>[C:36]([O:35][C:33](=[O:34])[NH:40][CH2:41][CH2:42][C:43](=[O:44])[NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (2.6 g, 16.8 mmol) was added to a stirred solution of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6 dione hydrochloride (2.0 g, 6.5 mmol) in DMF (100 mL). After stirring for 10 minutes, 1-hydrocybenztriazole (1.1 g, 7.8 mmol) and N—BOC-β-alanine (1.4 g, 7.1 mmol) were added. The reaction was initiated by addition of 1-[3-(dimethylamino0propyl]-3-ethylcarbodiimide hydrochloride (1.9 g, 9.7 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with H2O (40 mL) and CH2Cl2 (120 mL). The solid was collected to give (2-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-ethyl)-carbamic acid t-butyl ester (2.1 g, 73%) as a white solid: mp 203-205° C.; 1H NMR (DMSO-d6) δ 1.36 (s, 9H, 3CH3), 1.99-2.04 (m, 1H), 2.27-2.64 (m, 2H), 2.85-2.98 (m, 1H), 3.00-3.18 (m, 2H), 4.31 (d, J=5.3 Hz, 2H, CH2), 4.33-4.53 (dd, J=17.3 and 37.3 Hz, 2H, CH2), 5.10-5.17 (dd, J=4.8 and 13.1 Hz, 1H, CH), 6.79 (t, 1H, NH), 7.47-7.52 (m, 2H, Ar), 7.61-7.64 (m, 1H, Ar), 8.43 (t, J=5.3 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.54, 28.19, 31.17, 35.60, 36.67, 46.15, 51.55, 77.77, 121.60, 128.24, 130.56, 131.61, 134.56, 140.04, 155.43, 168.02, 170.43, 170.95, 172.80; Anal. calcd. for C22H28N4O6: C, 59.45; H, 6.35; N, 12.60. Found: C, 59.16; H, 6.31; N, 12.50.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][SH:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:14]([SH:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:14]([S:22][S:13][CH2:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCCc1ccccc1
Reactant: SCCCc1ccc2c(c1)OCO2
Product: c1ccc(CCSSCCCc2ccc3c(c2)OCO3)cc1
Yield: 17.7 %

Procedure:
1.5 g of the title compound was prepared from 5 g of 3-(1,3-benzodioxol-5-yl)propanethiol and 5 g of phenethyl mercaptan as a colorless oil according to the same procedure as that described in Example 1.