Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:21]([CH3:22])[CH3:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Reaction time: 18 h
Yield: 104.6 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (50 g, 0.27 mole), K2CO3 (74 g, 0.54 mole) and iodopropane (29.5 ml, 0.23 mole) were stirred at room temperature in DMF (100 mL). After 18 hours, the solvent was removed by evaporation under vacuum and the residue was chromatographed over a column of silica 60 in EtOAc/hexane (1:1) to give the title compound as an oil (55 g, 90%). 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d), 7.89 (1H, dd), 6.94 (1H, d), 4.60-4.72 (1H, m), 3.89 (3H, s), 1.41 (6H, d); m/z (API-ES) 229 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29])=[O:22].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1[C:10]2[C@@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH2:29])=[O:22])[CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: Nc1ccccc1C(=O)CCCCl
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccccc1C(=O)CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCC3
Yield: 16.5 %

Procedure:
The title compound (0.031 g, 16%) was prepared by the general method of Example 402 from (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.11 g, 0.50 mmol), 4-chloro-2′-aminobutyrophenone (0.20 g, 1.0 mmol), KI (catalytic) and K2CO3 (0.14 g, 1.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.80-2.20 (m, 7H), 2.20-2.60 (m, 3H), 2.82-2.95 (m, 1H), 2.98 (t, J=7.4 Hz, 2H), 3.05-3.20 (m, 2H), 3.20-3.38 (m, 2H), 3.64 (t, J=6.6 Hz, 1H), 3.68-3.80 (m, 1H), 3.81 (t, J=6.0 Hz, 1H), 6.26 (br, 2H), 6.58-6.68 (m, 2H), 6.80-6.92 (m, 2H), 7.10-7.30 (m, 2H), 7.52-7.72 (m, 1H), 7.77 (dd, J=1.3, 8.4 Hz, 1H), 8.09 (td, J=1.6, 8.4 Hz, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17](F)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([SH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1SCc1ccccc1
Temperature: 90 °C
Yield: 80 %

Procedure:
To a solution of 5-(3,5-dichlorophenyl)-3-(4-fluoro-3-methylphenyl)-4,5-dihydro-5-(trifluoromethyl)isoxazole (i.e. the product from Step B of Example 2) (2.6 g, 6.65 mmol) and potassium carbonate (2.3 g, 16.6 mmol) in N,N-dimethylformamide (25 mL) was added benzyl mercaptan (0.782 mL, 6.65 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was then cooled and excess-water was added, and the mixture was extracted with ethyl acetate (2×100 mL). The organic extracts were dried (MgSO4) and concentrated under reduced pressure to provide a solid residue. The crude product was partially purified by silica gel column chromatography eluted with mixtures of hexane and ethyl acetate to afford a product containing the title compound (about 80% purity, 2.8 g).
Reaction SMILES: N[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1.N1CCC(C[C:39]([NH2:41])=[O:40])CC1>>[C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:11]3[N:10]=[C:9]([N:6]4[CH2:5][CH2:4][CH:3]([CH2:2][C:39]([NH2:41])=[O:40])[CH2:8][CH2:7]4)[C:14]([F:15])=[CH:13][N:12]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:25]1)(=[O:31])[CH3:30]
Reactant: NC(=O)CC1CCNCC1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CN)CC4)n3)cc2)CC1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CC(N)=O)CC4)n3)cc2)CC1

Procedure:
The titled compound was synthesized analogously as compound 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, by using 2-(piperidin-4-yl)acetamide. MS 456.3 (M+H); UV 203.8, 269.8 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=O)=[C:4]([F:20])[CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[F:31])[NH:27][N:26]=[CH:25]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:30]=2[F:31])[NH:27][N:26]=[CH:25]3)=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: Nc1cc2cn[nH]c2cc1F
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(Cl)cc2F)CC(=O)N1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.5 %

Procedure:
The product of Example 48, Step 2 (200 mg, 0.672 mmol, 1.00 equiv), 5-amino-6-fluoroindazole (102 mg, 0.672 mmol, 1.0 equiv), and EDC (154 mg, 0.806 mmol, 1.20 equiv) were suspended in 1.5 mL DMF. Et3N (0.112 mL, 0.806 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (0-80% EtOAc in Hexanes) to provide 13 mg (4%) of the title compound as a white solid. MS (ES+) m/e 431 [M+H]+
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[NH4+].[Cl-].C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)CO)=CC=C([N+]([O-])=O)C=1.C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N>C1N(CCCS(O)(=O)=O)CCOC1>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
L-tyrosine production experiments were performed at 37° C. with 225 rpm orbital shaking in 50 ml MOPS minimal medium (Teknova) (Neidhardt, Bloch et al. 1974) cultures supplemented with 5 g/l glucose and an additional 4 g/l NH4Cl. All liquid cultivations were conducted in at least triplicates. When appropriate, antibiotics were added in the following concentrations: 34 μg/ml chloramphenicol for maintenance of pHACM-derived plasmids and 20 μg/ml kanamycin for maintenance of pZE-derived plasmids. L-phenylalanine auxotrophic (ΔpheA) cultures were additionally provided with L-phenylalanine (Sigma) at a concentration of 0.35 mM.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH:11]([CH3:13])[CH3:12]>>[CH:11]([C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9])([CH3:12])[CH3:10]
Reactant: CC(C)C(=O)O
Reactant: Cc1ccnc(N)c1N
Product: Cc1ccnc2nc(C(C)C)[nH]c12

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and isobutyric acid (0.19 ml, 2 mmol) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (20:1) to give the pure product (0.25 g, 72%) as a tan colored solid.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:22]=1>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCc1cccnc1
Product: COc1cc(CNCCc2cccnc2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 58.3 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-(pyridin-3-yl)ethylamine (0.0224 g, 0.184 mmol) gives the title compound (0.0406 g, 58.4%): TOF MS ES+ 379.2 (M+H)+, HRMS calcd for C21H23N4O3 379.1770 (M+H)+, found 379.1759, time 0.41 min.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](O)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CO>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([CH2:16][OH:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: OCc1onc(-c2ccccc2)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 1 g, 3.89 mmol) in THF (10 mL), cooled to −10° C., was added N-methylmorpholine (0.470 mL, 4.28 mmol) followed by isobutyl chloroformate (0.562 mL, 4.28 mmol) over a period of 3 min. After 15 min. at −10° C., this heterogeneous reaction mixture was added to a suspension of sodium borohydride (0.191 g, 5.06 mmol) in THF (12 mL) and methanol (3.0 mL) at −78° C. over a period of 10 min. using a Pasteur pipette. The reaction mixture was stirred at −78° C. for 10 min. The reaction mixture was allowed to warm to −20° C. over a period of 30 min. and quenched by the slow addition of AcOH in water (1:9 mL). The reaction mixture was allowed to come to room temperature, concentrated under reduced pressure and the residue partitioned between ethyl acetate (60 mL) and water (10 mL). The ethyl acetate layer was separated and washed sequentially with sat. aq. sodium bicarbonate (10 mL), brine (10 mL), dried over sodium sulfate and concentrated. The resulting oil was subjected to silica gel column chromatography using hexane/ethyl acetate to yield (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (0.44 g, 1.809 mmol, 46.5% yield) as an oil. 1H NMR (500 MHz, CDCl3) δ ppm 2.21 (br. s., 1H), 4.97 (s, 2H), 7.47-7.56 (m, 3H), and 7.65 (d, J=6.60 Hz, 2H); LCMS M+1=244.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)[CH:56]=2)[CH:51]=[CH:50]1>CN(C=O)C>[NH:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)[CH:56]=2)[CH:51]=[CH:50]1
Reactant: Nc1cccc(-c2ccc3cc[nH]c3c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
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: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3cc[nH]c3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 58.2 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-6-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 58% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: [CH3:1][CH:2]([NH2:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.ON1C2C=CC=CC=2N=N1.[C:23](O)(=[O:32])[C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:25][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:12][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:32]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CC(N)CCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Temperature: -5 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a cooled (-5° C.) solution of 32 g of the above enriched amine, 33 g of 1-hydroxybenzotriazole and 31.22 g of (R)-mandelic acid in 350 mL of dimethylformamide, was added a solution of 44.26 g of 1,3-dicyclohexylcarbodiimide in 150 mL of dimethylformamide and the mixture was stirred at -5° C. for 18 hours. After the precipitated dicyclohexylurea was removed by filtration, the filtrate was evaporated and the residue dispersed in 300 mL of cold 2N sodium hydroxide. The resulting solids were removed by filtration, washed with dilute sodium hydroxide solution and with water and then dissolved in 500 mL of 2N hydrochloric acid. The acidic solution was extracted with dichloromethane (3×150 mL) to remove neutral impurities, then was basified with 10N sodium hydroxide and extracted with dichloromethane (6×300 mL). The dried extracts were evaporated to give 55 g of residual solid. Crystallization of the product from ethanol gave 25.6 g of [ R-(R*,R)]-alpha-hydroxy-N-[1-methoxy-4-(3-pyridinyl)butyl]benzeneacetamide, mp 141°-143° C. An additional 1.3 g of product, mp 141°-143° C., was obtained from the mother liquors.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C[N+]1C2C(=CC=CC=2)N=C2C=1C=CC=C2.COS([O-])(=O)=O>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C:3]([CH:2]=[O:1])=[O:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: COS(=O)(=O)[O-]
Agent: C[n+]1c2ccccc2nc2ccccc21
Agent: O=P([O-])([O-])[O-]
Product: O=CC(=O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The reaction mixture containing 400 ml of purified membrane-bound L-sorbose dehydrogenase (total activity, 120 units), as prepared by the manner as described in steps (1) to (5) of Example 1, 50 ml of 0.5M potassium phosphate buffer (pH 6.0). 50 ml of 1M L-sorbose solution and 10 ml of 0.2M phenazine methosulfate solution was incubated at 30° C. with gentle shaking. As a result, L-sorbosone was formed with the rate of 224 mg/hr.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[C:3]=1[CH3:12].[Cu][C:14]#[N:15]>CN1CCCC1=O.ClCCl>[Br:11][C:4]1[C:3]([CH3:12])=[C:2]([C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[C:14]#[N:15]
Reactant: N#C[Cu]
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1Br
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1c(Br)ccc([N+](=O)[O-])c1C#N
Temperature: 150 °C

Procedure:
To a mixture of 2,6-dibromo-3-nitrotoluene (1.0 g, 3.4 mmol) in 14 ml of N-methylpyrrolidinone was added 0.323 g of freshly prepared copper (I) cyanide. The reaction was stirred and heated at a temperature of 150° C. under a nitrogen atmosphere for a period of three hours. After this period, the reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with 10% aqueous sodium thiosulfate solution. The organic layer was separated, dried, and concentrated under vacuum to remove the solvent. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate/80% hexane, to afford 0.293 g of 3-bromo-2-methyl-6-nitrobenzonitrile as a yellow-white crystalline solid, mp 116°-118° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].S=[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:31]1[C:32]([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[C:32]([O-:34])(=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:30]=1
Reactant: O=C([O-])C1C=CC=CC1=S
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C([O-])c1ccccc1

Procedure:
5-Cholesten-3β-ol-thionobenzoate (100 mg, 0.198 mmol), symdibromo-tetrachloroethane (323 mg, 0.991 mmol), and 4-methoxy-4'-dimethylaminodiphenyltellurium dichloride (8.4 mg, 0.0198 mmole) were stirred in a two phase system of chloroform (2 ml) and aqueous potassium carbonate (2.5 ml, 20%) at room temperature for 4 h. T.l.c. (petroleum ether followed by petroleum ether-ethyl acetate 20:1) showed complete reaction. The two phases were separated, the aqueous phase extracted with chloroform (2×5 ml) and the combined chloroform extracts dried over magnesium sulphate. Filtration, evaporation of the solvent and column chromatography (petroleum ether followed by petroleum ether-ethyl acetate 20:1) of the residue afforded 5-cholesten-3β-ol-benzoate (85 mg, 88%) m.p. 143°-145° (lit; 150°-151°). The i.r. spectrum was identical to that of an authentic sample.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH2:7][O:6][C:5]2[N:10]=[C:11]([C:20]3[CH:34]=[CH:33][C:23]([CH2:24][NH:25]C(=O)OC(C)(C)C)=[CH:22][CH:21]=3)[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:4]1=2)[CH3:2]>C(O)(C(F)(F)F)=O>[NH2:25][CH2:24][C:23]1[CH:33]=[CH:34][C:20]([C:11]2[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]3[N:3]([CH2:1][CH3:2])[C:8](=[O:9])[CH2:7][O:6][C:5]=3[N:10]=2)=[CH:21][CH:22]=1
Reactant: CCN1C(=O)COc2nc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(-c3ccccc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)COc2nc(-c3ccc(CN)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 99.4 %

Procedure:
tert-Butyl 4-(1-ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzylcarbamate (45 mg, 0.098 mmol) was dissolved in TFA (1 mL). The resulting mixture was stirred for 30 seconds at room temperature and evaporated under reduced pressure. The deprotected compound was taken back twice into diethyl ether and the solid formed was washed twice with diethylether. The remaining solvent was removed under reduced pressure and dried to afford the title compound (35 mg, 99%) as white solid. LCMS: RT=0.75 min, M+H+=360. 1H NMR (500 MHz, CDCl3): 8.34 (2H, br), 7.30-7.27 (5H, m), 7.18 (3H, m), 7.13-7.11 (2H, m), 4.80 (2H, s), 4.03-3.99 (2H, q), 3.96 (2H, s), 1.32-1.30 93H, t).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.[BH4-].[Na+].[ClH:31]>CO>[ClH:31].[C:15]1([CH2:21][CH2:22][CH2:23][NH:24][CH:10]([CH3:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCCc1ccccc1
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(Cc1cccc(C(F)(F)F)c1)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 1-(3-trifluoromethylphenyl)-2-propanone (102 mg, 0.50 mmol), 3-phenyl-1-propylamine (86 mg, 0.64 mmol), glacial acetic acid (8 mg, 0.13 mmol), and MeOH (2 mL) was allowed to stir at room temperature for 0.5 h. To this mixture was added over a 4-h period sodium borohydride (19 mg, 0.50 mmol) and the mixture was allowed to stir at room temperature for 20 h. The solvents were removed by warming under reduced pressure to give a small amount of an oil which was cooled and treated with 10% HCl. The crude product separated as a white solid, 122 mg (68%), mp 135-145° C. The crystals were dissolved in H2O and the solution was extracted with Et2O. The H2O portion was separated, the H2O was evaporated, and the crystals reformed; recrystallization from acetone gave 66 mg (37%) of colorless crystals, mp 167-169° C.
Reaction SMILES: [OH:1][CH:2]([CH:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:7]=2[CH2:6]1)[CH2:3][OH:4].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[OH:1][CH:2]([CH:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:7]=2[CH2:6]1)[CH2:3][O:4][S:28]([C:21]1[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[CH3:19])(=[O:30])=[O:29]
Reactant: COC(=O)Cc1ccc2c(c1)CC(C(O)CO)O2
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc2c(c1)CC(C(O)COS(=O)(=O)c1c(C)cc(C)cc1C)O2
Reaction time: 8 h

Procedure:
The compound of Example 7, (430 mg, 1.7 mmoles) was taken up in dry pyridine (20 ml) and cooled to 0° under N2. 2,4,6-Trimethylphenylsulfonyl chloride (400 mg) was added at 0° and stirring was continued overnight at 0°. Additional 2,4,6-trimethylphenylsulfonyl chloride (75 mg) was added, and stirring was continued at 5° for 24 hours. The pyridine was removed under high vacuum and the residue was taken up in CHCl3, washed with dilute HCl, brine, dried and concentrated. Chromatography of the residue on silica gel using ethyl acetate gave the title compound as a mixture of the two diastereoisomers. NMR (90 MHz) (CDCl3) (ppm) 2.37 (3H, s), 2.67 (6H, s), 2.5-2.8 (1H, br), 3.27 (2H, d), 3.57 (2H, s), 3.70 (3H, s), 3.9-4.3 (3H, m), 4.75 (1H, m), 6.73 (1H, d), 6.97-7.25 (4H, m).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]1[C:9]2=[C:10]([S:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:11]3[C:12]([CH:25]([CH3:27])[CH3:26])=[CH:13][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.CC(O)=O>C1COCC1.CO.[Li+].[OH-]>[CH2:18]([O:17][C:14]1[CH:13]=[C:12]([CH:25]([CH3:27])[CH3:26])[C:11]2[C:10]([S:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[C:9]3[CH:5]([CH2:4][C:3]([OH:36])=[O:2])[CH2:6][CH2:7][N:8]3[C:16]=2[CH:15]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)C)cc(OCc3ccccc3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1cc(OCc2ccccc2)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of the ester of Step 5 100 mg in THF/MeOH (3/1) mixture at r.t. was added in LiOH aqueous solution 1.0 mL. The reaction mixture was stirred at r.t. for 1 hour then AcOH was added and the solvent was evaporated. The residue was taken up in EtOAc/H2O and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by silica gel chromatography, eluting with 1% AcOH in EtOAc to give 70 mg of the title compound.