Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:7][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:28])=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCC(=O)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1conc1-c1ccc(OCC(=O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 64 %

Procedure:
{3-[4-(2-Oxo-2-phenyl-ethoxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (70 mg, 0.18 mmol) was dissolved in dioxane (1 mL) and treated with 4N HCl in dioxane (1 mL, 4 mmol). After stirring overnight the resulting white solid was removed by filtration and washed with hexanes to yield 2-[4-(4-Amino-isoxazol-3-yl)-phenoxy]-1-phenyl-ethanone hydrochloride as a white solid (34 mg, 64%). MH+=295.0
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH:40][CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)CCCN
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)CCCCCCCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
A mixture of 12-tert-butoxycarbonylaminododecanoic acid (3) (205 mg, 0.65 mmol) and 1,1′-Carbonyldiimidazole (114 mg, 0.70 mmol) in anhydrous THF (5 mL) was stirred at room temperature for 3 hours. 3-(Dimethylamino)propylamine (163 mL, 1.30 mmol) was then added via syringe and the reaction mixture stirred at room temperature for a further 24 hours. The solvent was then removed by rotary evaporation and the residue subjected to Biotage silica gel column chromatography (ethyl acetate/dichloromethane 5% to 75%, then methanol/dichloromethane 8%) to give the desired amide 4 (87.0 mg, 34%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 14H), 1.45 (s, 9H), 1.47 (m, 2H), 1.60 (m, 2H), 1.69 (m, 2H), 2.16 (t, 2H), 2.29 (s, 6H), 2.45 (t, 2H), 3.10 (m, 2H), 3.32 (m, 2H), 4.50 (br, 1H), 6.91 (br, 1H). m/z (ESI) 400 [C22H45N3O3+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@@H:9]1[C:19](O)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][C@@H:9]1[CH2:19][OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)O)CC[C@H]1c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To an ice cold solution of commercially available (2R,5S)-5-phenyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.00 g, 3.45 mmol) in 1,2-dimethoxyethane (5 mL) is added 4-methylmorpholine (0.4 mL, 3.795 mmol) and isobutyl chloroformate (0.50 mL, 3.795 mmol). Stir 15 min and filter into cold flask. Add sodium borohydride (0.196 g, 5.17 mmol) in water (3 mL), followed by addition of water (50 mL). Extract product with ethyl acetate (3×50 mL) and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and purify on silica gel to give the title compound (0.886 g, 93%).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](O)=[O:5].[CH2:9]([C:12]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:13]=1[OH:14])[CH2:10][CH3:11]>OS(C(F)(F)F)(=O)=O>[OH:14][C:13]1[CH:15]=[CH:16][C:17]([C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:18]([OH:19])[C:12]=1[CH2:9][CH2:10][CH3:11]
Reactant: CCCc1c(O)cccc1O
Reactant: CC(C)(C)CC(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Product: CCCc1c(O)ccc(C(=O)CC(C)(C)C)c1O

Procedure:
Using the procedure in Example 51, step 1, 3,3-dimethylbutyric acid and 2-(n-propyl)resorcinol were condensed in triflic acid to form 1,3-dihydroxy-4-(3,3-dimethylbutyryl)-2-(n-propyl)benzene
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.Cl[Si](C)(C)C.[CH2:24]([CH:26]1[O:28][CH2:27]1)Br.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:11][CH2:24][CH:26]3[CH2:27][O:28]3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrCC1CO1
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1cc(C2CCCCC2)ccc1NCC1CO1
Temperature: -72.5 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
To a stirred solution of 4-cyclohexylaniline (5 g, 28.6 mmol) in 75 ml of dry THF at −70 to −75° C. was added slowly by syringe a solution of 17.7 ml of 1.6 M n-butyllithium. When addition was complete, the resulting mixture was stirred at −70 to −75° C. for 0.5 h. To the stirred mixture was then added 3.61 ml (28.5 mmol) of chlorotrimethylsilane at −70 to −75° C. The mixture was then allowed to warm to RT and stirred at RT for 1.75 h. The mixture was then again cooled to −70 to −75° C. after which was slowly added 17.5 ml of 1.6 M n-butyllithium in hexanes. The mixture was allowed to stir at −70 to −75° C. for 0.5 h after which was added 2.45 ml (28.6 mmol) of epibromohydrin. The mixture was allowed to warm to room temperature and stirred for 2 h at room temperature. The mixture was then poured into 250 ml of cold saturated aqueous sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried (sodium sulfate) and concentrated to provide an orange oil which was then purified by chromatography on silica gel, eluting with ethyl acetate/heptane to provide 3.06 g of the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.Cl.[NH2:13][C:14]1[C:15]([Cl:22])=[C:16]([OH:21])[C:17]([CH3:20])=[CH:18][CH:19]=1.OO.[OH-].[NH4+]>O.C(O)C>[NH2:13][C:14]1[C:19](=[N:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][CH3:3])=[CH:6][CH:7]=2)[CH:18]=[C:17]([CH3:20])[C:16](=[O:21])[C:15]=1[Cl:22]
Reactant: CNc1ccc(N)cc1
Reactant: Cc1ccc(N)c(Cl)c1O
Agent: Cl
Agent: OO
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CNc1ccc(N=C2C=C(C)C(=O)C(Cl)=C2N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.4 %

Procedure:
A mixture of 2 g of N-methylbenzene-1,4-diamine dihydrochloride, 2 g of 3-amino-2-chloro-6-methylphenol hydrochloride, 20 ml of water, 20 ml of ethanol and 7.6 ml of 9% aqueous hydrogen peroxide solution, a mixture brought to pH 9.5 with 20% ammonium hydroxide in water, is stirred at ambient temperature for 5 hours. 2.5 g of 3-amino-2-chloro-6-methyl-4-{[4-(methylamino)phenyl]imino}cyclohexa-2,5-dien-1-one (1n) are obtained.
Reaction SMILES: [CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[Se](=O)=O>C(O)(C)(C)C>[CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Agent: O=[Se]=O
Solvent: CC(C)(C)O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Yield: 40.3 %

Procedure:
A mixture of 6-methylenandrost-4-ene-3,17-dione (0.50 g), selenium dioxide (0.50 g) and t-butylalcohol (200 ml) was heated to reflux under nitrogen for about 30 hours. The cooled solution was filtered and then evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate (100 ml), treated with charcoal and washed consecutively with water, ammonium sulfide solution, cold 17% ammonium hydroxide, cold dilute hydrochloric acid, water, dried with sodium sulfate and finally evaporated to dryness. The crude product was chromatographed as described in example 1 to yield 0.20 g of pure 6-methylenandrosta-1,4-diene-3,17-dione, m.p. 188°-191° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>CS(C)=O.N.[Cu].[Pd](Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([O-:3])=[O:2]
Reactant: Brc1ccccn1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]
Agent: N
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1-c1ccccn1
Reaction time: 0.5 h
Yield: 11.8 %

Procedure:
A solution of 2-nitrobromobenzene (2.02 g), 2-bromopyridine (0.80 g), copper powder (1.29 g), and palladium dichloride (0.049 g) in 15 mL of DMSO was heated at 120° C. under N2 for 2 hours. Once cooled, the mixture was diluted with 100 mL of 10% aqueous ammonia and stirred for 30 min. This mixture was filtered, and the filtrate was extracted several times with CHCl3. The combined extracts were dried (Na2SO4) and evaporated. The crude product was purified by chromatography on silica gel with 20% EtOAc/hexanes to yield 0.12 g (22%) of 2-(2-Nitrophenyl)pyridine. [This compound was reported by Molina, Pedro; Lorenzo, Angeles; Aller, Enrique; Tetrahedron; 1992, 48, (22), 4601-4616.]
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([CH:44]=[O:45])[CH:51]=2)=[CH:3][C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:14]=2)=[O:12])=[CH:5][CH:6]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(Br)c2)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)c1
Yield: 58.4 %

Procedure:
N-[(3-Bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (868 mg, 1.3 mmol), (3-formylphenyl)boronic acid (195 mg, 1.300 mmol), potassium carbonate (539 mg, 3.90 mmol), and Pd(Ph3P)4 (75 mg, 0.065 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixtures were microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated, and the organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4 filtered and evaporated to give the crude residue. The residue was taken up in DCM and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give (N-[(6-chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (531.4 mg, 0.759 mmol, 58.4% yield) as a white solid. LC-MS m/z 693.4 (M+H)+, 1.01 min (ret time); mp 153-156° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([CH3:8])=[N:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[N:4]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:25][C:26]([F:43])([F:42])[C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][N:28]=1>O1CCCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[N:5]1[N:4]=[C:3]([CH2:2][C:31]2[CH:30]=[CH:29][N:28]=[C:27]([C:26]([F:43])([F:42])[F:25])[CH:32]=2)[C:7]([CH3:8])=[N:6]1
Reactant: CC1(C)OB(c2ccnc(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1nn(-c2ccc(F)cc2F)nc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2ccc(F)cc2F)nc1Cc1ccnc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
To a solution of 4-(bromomethyl)-2-(2,4-difluorophenyl)-5-methyl-2H-1,2,3-triazole (i.e. the product of Step C, 0.30 g, 1.0 mmol) in tetrahydrofuran/water (3:1, 4 mL total), was added tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol), potassium phosphate tribasic (0.43 g, 2.0 mmol) and 2-(trifluoromethyl)pyridine-4-boronic acid pinacol ester (0.31 g, 1.15 mmol). The mixture was heated to 70° C. and stirred for 96 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by twice by chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes, and then was purified by reverse-phase chromatography on C18 silica gel to afford the title compound (0.18 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[F:24]NS(C1C=CC=CC=1)(=O)=O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][C:3]=1[F:24]
Reactant: O=S(=O)(NF)c1ccccc1
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Solvent: CN(C)C=O
Product: Nc1nc2[nH]c(-c3ccc(F)cc3)c(-c3ccncc3)c2cc1F
Reaction time: 48 h

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (250 mg, 0.822 mmol), N-fluorobenzenesulphonamide (259 mg, 0.822 mmol), and DMF (4 mL) were warmed to 90° C. behind an explosion shield. After 48 h, the reaction was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate: hexane 1:1) to afford 6-Amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (28): Mass Spectrum (CI) 323 (MH+).
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.O.[CH2:32](O)[CH2:33][OH:34]>C1C=CC=CC=1>[O:11]1[CH2:32][CH2:33][O:34][CH:10]1[C:9]1[CH:12]=[CH:13][C:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:14]([CH3:16])[CH3:15])[CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=1
Reactant: CC(C)[Si](Oc1ccc(C=O)cc1)(C(C)C)C(C)C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)[Si](Oc1ccc(C2OCCO2)cc1)(C(C)C)C(C)C

Procedure:
Heat at reflux a mixture of the aldehyde (2.1033 g, 7.55 mmol), p-TsOH.H2O (14.4 mg, 0.076 mmol), and ethylene glycol (4.2 mL, 75.5 mmol) in benzene (75 mL) overnight, while removing azeotropically the H2O formed. Cool and wash with 10% K2CO3 (2×50 mL) and brine which contains 10% K2CO3 (50 mL). Back-extract the aqueous layers with benzene and Et2O (100 mL each). Concentrate the combined organic layers after drying over Na2SO4 to afford (4-[1,3]dioxolan-2-yl-phenoxy)triisopropylsilane.
Reaction SMILES: [CH:1]1([O:7]/[N:8]=[C:9](/[C:15](=[O:17])[CH3:16])\[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])(=O)=O>>[Cl:21][CH2:16][C:15](=[O:17])/[C:9](=[N:8]/[O:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)C(C)=O
Product: CCOC(=O)/C(=N\OC1CCCCC1)C(=O)CCl
Temperature: 25 °C
Yield: 60 %

Procedure:
Ethyl (Z)-2-(cyclohexyloxyimino)-3-oxobutyrate (1.0 g) was added to ice-cooled sulphuryl chloride (10 ml) with stirring. The mixture was allowed to warm to room temperature, stirred for 27 h, then evaporated under an argon stream. The residue was dissolved in diethyl ether, washed twice with water, then brine, dried (MgSO4) and evaporated. Purification by flash chromatography, eluting with dichloromethane/carbon tetrachloride gave the title compound (0.69 g, 60%) as a colourless liquid; νmax (film) 2950, 2860, 1750, 1720 cm-1 ; δH (CDCl3) 1.32 (3H, t), 1.2-2.0 (10H, br m), 4.3 (1H, br m), 4.34 (2H, q), and 4.53 (2H, s), (Found: MH+ 276.0998, C12H18NO4Cl requires M+H 276.1004).
Reaction SMILES: [N:1]1([C:7](=[O:9])[CH3:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10](#[N:13])[CH:11]=[CH2:12]>CO>[C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:12][CH2:11][C:10]#[N:13])[CH2:3][CH2:2]1)(=[O:9])[CH3:8]
Reactant: C=CC#N
Reactant: CC(=O)N1CCNCC1
Solvent: CO
Product: CC(=O)N1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.5 %

Procedure:
To 1-(piperazin-1-yl)ethanone (5 g, 39 mmol) in MeOH (50 mL) at 0° C. is added acrylonitrile (2.57 mL, 39 mmol) in one portion. The resulting reaction is stirred for 12 hours while allowing the reaction to warm to room temperature. The reaction mixture is concentrated in vacuo and the resulting residue diluted with 5 mL of water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified over silica (2% MeOH in CH2Cl2) to afford 6.4 g (91% yield) of the desired compound. 1H NMR (CDCl3, 300 MHz) δ2.08 (s, 3H), 2.46 (t, J=5.1 Hz, 2H), 2.51-2.53 (m, 4H), 2.71 (t, J=6.9 Hz, 2H), 3.48 (t, J=5.1 Hz, 2H), 3.26 (t, J=5.1 Hz, 2H). MS (ESI, pos. ion) m/z: 182 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][C@@H:8]1[O:13][C@H:12]([CH3:14])[CH2:11][N:10](CC=C)[C@@H:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(#N)C.O>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[CH2:6][O:7][C@@H:8]1[O:13][C@H:12]([CH3:14])[CH2:11][NH:10][C@@H:9]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CCN1C[C@@H](C)O[C@@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN[C@H](c2ccccc2)[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Yield: 63.9 %

Procedure:
A solution of 115 mg (0.25 mmol) of the 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)-6-(R)-methyl morpholine (from Example 23, Step A) and 230 mg (0.25 mmol) of tris(triphenylphosphine)rhodium chloride in 15 mL of 4:1 v/v acetonitrile/water was heated at reflux for 30 min. The reaction was cooled and partitioned between 50 mL of ethyl acetate and 15 mL of water. The layers were separated and the organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 2×25 mL of ethyl acetate; the extracts were dried and combined with the original organic layer. The combined organics were concentrated in vacuo. The residue was filtered through a pad of silica gel (~20 g) using 2:1 v/v ether/hexanes as the solvent. The filtrate was concentrated; flash chromatography on 5 g of silica gel using 17:3 v/v hexanes/ether as the eluant afforded 67 mg (64%) of 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methyl morpholine as an oil.
Reaction SMILES: [O:1]=[C:2]([CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[N:15]([CH3:19])[CH:14]=[N:13][C:12]=2[N:11]([CH3:20])[C:9]1=[O:10].[BH4-].[Na+]>>[OH:1][CH:2]([CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[N:15]([CH3:19])[CH:14]=[N:13][C:12]=2[N:11]([CH3:20])[C:9]1=[O:10]
Reactant: CC(=O)CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O

Procedure:
Racemic 1-(6-hydroxyheptyl)-3,7-dimethylxanthine (melting point: 76°-77° C.) was prepared for comparison by reduction of 1-(6-oxoheptyl)-3,7-dimethylxanthine with NaBH4 analogously to d).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>CN(C=O)C.C1COCC1>[CH2:21]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1])[CH2:20][CH:19]=[CH2:18]
Reactant: C=CCCBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCCN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (0.500 mg, 2.50 mmol) in 10 mL of DMF at 0° C. was added NaH as a 60% dispersion in mineral oil (2.62 mmol), and the reaction was stirred for 45 minutes. 4-Bromo-1-butene was added (0.280 mL, 2.75 mmol) dropwise as a solution in 1 mL of THF. The solution was stirred overnight, allowing it to warm to room temperature. The reaction was partitioned between EtOAc and saturated NaHCO3 solution. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 255.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19]=[O:20])[NH:11][CH:10]=[C:9]1[C:21]([O:23][CH3:24])=[O:22].[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH2:19][OH:20])[NH:11][CH:10]=[C:9]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CCOC(=O)C1=C(C=O)NC=C(C(=O)OC)C1c1ccccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(CO)NC=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 0.83 h
Yield: 55.6 %

Procedure:
To a mixture of powder (329 mg) of methyl 4-(2-chlorophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate in ethanol (10 ml) was added sodium borohydride (25.11 mg) under ice-cooling. After further stirring for 50 minutes, the mixture was adjusted to pH 4 to 5 with dilute hydrochloric acid. After removal of the ethanol, water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried and the residual crystals (about 280 mg) were dissolved in a mixture of diethyl ether and n-hexane and kept in a refrigerator to give pure crystals (184 mg) of methyl 4-(2-chlorophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 187 to 188° C.
Reaction SMILES: CN(C)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:6].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1>CCO.O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)=[O:6])[CH3:23])=[CH:18][CH:17]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: CN(C)CCC(=O)c1cccc(F)c1
Solvent: CCO
Solvent: O
Product: C[C@H](NCCC(=O)c1cccc(F)c1)c1ccc(Br)cc1
Temperature: 80 °C
Yield: 20.3 %

Procedure:
A solution of 3-dimethylamino-1-(3-fluoro-phenyl)-propan-1-one (17 g, 0.087 mol) and (S)-1-(4-bromophenyl)-ethanamine (17 g, 0.087 mol) in a mixture of EtOH (50 mL) and H2O (50 mL) was refluxed at 80° C. overnight. The solvent was removed under vacuum, and the residue was purified by column chromatography to afford (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(3-fluorophenyl)-propan-1-one (6.2 g, 20%).