Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C@@H:18]1(N)[CH2:23][CH2:22]CC[C@H:19]1[NH2:24].C(=O)([O-])[O-:27].[K+].[K+].C1(C)C=CC=CC=1>[Cu]I.C(OCC)(=O)C>[O:27]=[C:19]1[CH2:18][CH2:23][CH2:22][N:24]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1(c2ccc(N3CCCC3=O)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2 mg, 1.0 mmol), t-oxo-pyrrolidine (1.2 mmol), copper(I) iodide (20.0 mg, 0.1 mmol), (trans)-cyclohexane-1,2-diamine (22.8 mg, 0.2 mmol) and potassium carbonate (300.0 mg, 2.17 mmol) was dearated under vacuum and then charged with nitrogen. To the mixture was added toluene (2.0 mL). The resulting mixture was heated at 100° C. for overnight. Then ethyl acetate (10 mL) was added to the mixture. The resulting mixture was filtered through a pad of celite, and the solid was washed with additional ethyl acetate. The filtrate was concentrated. The residue was purified by flash chromatography with ethyl acetate/hexane to afford tert-butyl 1-[4-(2-oxo-pyrrolidin-1-yl)phenyl]cyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]([CH3:11])=[N:8][C:6]=2[N:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CO.CCOC(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH3:11])=[N:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Cc1nc2nc(Cl)nc(Cl)c2s1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 5,7-dichloro-2-methyl-thiazolo[4,5-d]pyrimidine (92 mg, 0.42 mmol) in MeOH (3 mL) was added morpholine (81 μL, 0.93 mmol) and the mixture stirred at RT for 1 h. The reaction mixture was diluted with EtOAc and H2O. The organic layer was isolated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a cream solid (102 mg, 90%).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][C:21]#[C:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][CH2:8]1)([OH:4])([OH:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[O-:46][P:47]([O:50][P:51]([O-])([O-:53])=[O:52])(=[O:49])[O-:48].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][C:21]#[C:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][CH2:8]1)([O:3][P:51]([O:50][P:47]([OH:49])([OH:48])=[O:46])([OH:53])=[O:52])(=[O:4])[OH:2]
Reactant: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O)C(F)(F)F
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
Without being limiting in any way, monophosphate (6) can optionally be formed by treatment of 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′dideoxyuridine (5) with, for example, POCl3. 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′-dideoxyuridine-5′-monophosphate (6) can then optionally be treated with, for example, carbonyldiimidazole (CDI) followed by tetrabutylammonium pyrophosphate (TBAPP) under appropriate conditions to form 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′-dideoxyuridine-5′-triphosphate (7). It will be recognized by one of skill in the art that conversion of 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′dideoxyuridine (5) to triphosphate (7) can be accomplished by any method known in the art.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=C(C)[CH:6]=[CH:5]2.[Se](=O)=O.O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+].[C:30]([O:33][CH2:34]C)(=[O:32])[CH3:31]>O1CCOCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:31]([CH:30]([O:32][CH3:17])[O:33][CH3:34])[CH:6]=[CH:5]2
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: O=[Se]=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COC(OC)c1ccc2cc(Br)ccc2n1
Temperature: 100 °C
Yield: 90 %

Procedure:
To a solution of 6-bromoquinaldine (111 mg, 0.500 mmol) in 1,4-dioxane (8 mL) was added selenium dioxide (111 mg, 1.00 mmol), and the mixture was heated at 100° C. for 1 h. The reaction mixture was diluted with ethyl acetate, filtered through Celite pad, and concentrated under reduced pressure. To the residue were added methanol (15 mL) and p-toluenesulfonic acid monohydrate (99 mg, 0.52 mmol), and the mixture was heated to reflux for 1.5 h. Diluted aqueous sodium hydroxide was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford 6-bromo-2-(dimethoxymethyl)quinoline (127 mg, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O-:13])([O-])=O.[K+].[K+].[C:16](#[N:18])[CH3:17]>>[CH3:10][O:13]/[N:18]=[C:16](/[C:2]1[CH:9]=[CH:8][CH:5]=[CH:4][CH:3]=1)\[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC#N
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Product: CO/N=C(\COc1ccc(C=O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 87.5 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 20 mL of acetonitrile. To the stirred solvent was added 4-hydroxy-benzaldehyde (0.21 g, 1.72 mmol) and K2CO3 (0.46 g, 3.33 mmol). Then it was stirred for 5 min. 2-Bromo-1-phenyl-ethanone o-methyl-oxime (0.4 g, 1.7 mmol) was added. Then RM was heated to 80° C. and stirred at this temperature for 5 h. After completion of the reaction (reaction monitored by TLC), RM was concentrated by removal of the acetonitrile, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic layer washed with saturated brine solution (20 mL) and dried over anhydrous Na2SO4 and evaporated to dryness to get the title compound (0.4 g, Yield: 87.5%): MS (ESI, 120 eV): m/z=270.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 9.80 (s, 1H), 7.72-7.75 (d, 2H), 7.655-7.59 (m, 2H), 7.27-7.29 (m, 3H), 6.92-6.95 (d, 2H), 5.22 (s, 2H), 4.01 (s, 3H).
Reaction SMILES: N#N.[Br:3][C:4]1[C:11]([F:12])=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[F:13].CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:9][CH2:8][C:7]1[CH:10]=[C:11]([F:12])[C:4]([Br:3])=[C:5]([F:13])[CH:6]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(F)c(Br)c(F)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(F)c(Br)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-3,5-difluorobenzyl alcohol (100 mg, 0.45 mmol) in dry CH2Cl2 (3 mL) was treated at 0° C. with Et3N (0.081 mL, 0.58 mmol) followed by DMAP (5 mg, 0.045 mmol) and Ms-Cl (0.037 mL, 0.47 mmol). After stirring at 0° C. for 0.5 h and at rt for 0.5 h, the reaction was quenched with water (2 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-3,5-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (3 mL) and treated with NaN3 (29 mg, 0.45 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-3,5-difluorobenzene as a yellow oil. LC-MS-conditions 07: tR=0.90 min.
Reaction SMILES: C(O[C@@H:5]1[C@@H:10]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@H:9]([O:18][C:19](=[O:21])[CH3:20])[C@@H:8]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:7][C@@H:6]1Br)(=O)C.C(OCC)(=[O:30])C>>[C:19]([O:18][C@@H:9]1[C@@H:8]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:7][C:6]([OH:30])=[CH:5][C@H:10]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](NC(=O)C(F)(F)F)[C@@H]1OC(C)=O
Reactant: CCOC(C)=O
Product: CC(=O)OC[C@H]1OC(O)=C[C@@H](NC(=O)C(F)(F)F)[C@@H]1OC(C)=O
Reaction time: 2.5 h

Procedure:
2,4,6-Tri-O-acetyl-1-bromo-1,3-dideoxy-3-trifluoroacetamido-α-D-glucopyranose [Chem. Ber. 104, 1 (1971)] is added to the cooled mixture at 5°-15° and continued stirring for 2.5 hours at 5°. When the reaction is complete as measured by TLC (ethyl acetate-SSB, 1:2) the mixture is filtered over a pad of filter-aid and washed with methylene chloride.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1>CO.[Pd]>[CH:1]1([O:5][C:6]2[N:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(OC2CCC2)nc1
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: Nc1ccc(OC2CCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask containing 10% w/w Pd/C (485 mg) was gently flushed with argon while slowly adding MeOH (50 mL) along the sides of the flask, followed by the addition in ˜5 mL portions of a solution of 2-cyclobutoxy-5-nitro-pyridine (4.85 g, 25 mmol), as prepared in the previous step, in MeOH (30 mL). (Caution: Large scale addition of volatile organics to Pd/C in the presence of air can cause fire.) The flask was then evacuated one time and stirred under H2 balloon pressure for 2 h at rt. The reaction was then filtered, and the clear amber filtrate was concentrated, taken up in toluene (2×50 mL) to remove residual MeOH, and concentrated under reduced pressure to provide the crude title compound as a translucent dark brown oil with a faint toluene smell (4.41 g, “108%” crude yield). 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=3.0 Hz, 1H), 7.04 (dd, J=8.71 and 2.96 Hz, 1H), 6.55 (d, J=8.74 Hz, 1H), 5.04 (m, 1H), 2.42 (m, 2H), 2.10 (m, 2H), 1.80 (m, 1H), 1.66 (m, 1H). LC-MS (ESI): calcd mass 164.1, found 165.2 (MH+).
Reaction SMILES: [BH3:1].[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1>O1CCCC1>[CH:2]1([BH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: B
Reactant: C1=CCCCC1
Solvent: C1CCOC1
Product: B(C1CCCCC1)C1CCCCC1
Reaction time: 1.5 h

Procedure:
To a stirred, ice-cold solution of 1M borane in tetrahydrofuran (10 ml) was added, dropwise, a solution of 2 ml (1.64 g) of cyclohexene in 6 ml of dry tetrahydrofuran. The mixture was allowed to stir at 0°-5° C. for 1.5 hours. Tothe resulting slurry of dicyclohexylborane was added, dropwise a solution of 1.59 g of the allyl ether from Example 18 in 4 ml of tetrahydrofuran. The mixture was stirred at 0°-5° C. for 1 hour and at room temperature for 18 hours at which point 20 ml of 1M methanolic sodium acetate was added dropwise followed by 23.8 ml of 0.4M methanolic iodine. The resulting mixture was stirred at room temperature for 4 hours whereupon 3.1 ml of aqueous sodium thiosulfate was added. The reaction mixture was poured into water worked-up with ether in the usual manner. Chromatography of the crude product (4.4 g) on 100 g of silica gel afforded 1.71 g (76.7%) of racemic-3,4-dihydro-6-(3-iodopropoxy)2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid methyl ester as an oil, eluted with 19:1 and 9:1 hexane-ethyl acetate.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[C@@H:8]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[C@H:9]([CH:18]=O)[CH2:10][C:11]=1[C:12]1C=CC=[CH:14][N:13]=1.[CH2:28]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:4][C:3]1[CH:2]=[CH:1][C:12]([C:11]2[CH2:10][C@@H:9]([CH:18]=[CH2:28])[C@H:8]([O:20][Si:21]([CH2:22][CH3:23])([CH2:24][CH3:25])[CH2:26][CH3:27])[C:7]=2[CH3:6])=[N:13][CH:14]=1
Reactant: CC[Si](CC)(CC)O[C@@H]1C(C)=C(c2ccccn2)C[C@H]1C=O
Reactant: [Li]CCCC
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a pre-cooled (0° C.) solution of methyltriphenylphosphonium bromide (286 mg, 0.8 mmol, 2 equiv) in THF (3 ml) was added n-butyllithium (0.49 ml of 1.6 M solution in hexanes, 0.78 mmol, 1.95 equiv) dropwise. The reaction mixture was stirred at 0° C. for 30 min. A solution of crude aldehyde 30b (ca 0.4 mmol) in THF (1.5 ml) was added and the mixture was stirred at 0° C. for 30 min and quenched with a saturated aqueous ammonium chloride solution (3 ml). The solvent was removed under reduced pressure, and the aqueous residue was extracted with ethyl acetate (3×3 ml). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica (7% EtOAc/hexanes) afforded pure olefin 31b (96 mg, 73%) as a yellowish oil: [α]22D=−21.29 (c=0.7, CHCl3); TLC Rf=0.66 (silica gel, 33% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H), 7.44 (dd, J=1.8 Hz, 7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 5.95-5.88 (m, 1H), 5.12 (d, J=16.8 Hz, 1H), 5.04 (d, J=10.8 Hz, 1H), 4.54 (d, J=5.4 Hz, 1H), 2.97-2.93 (m, 1H), 2.74-2.68 (m, 1H), 2.60-2.56 (m, 1H), 2.30 (s, 3H), 1.96 (s, 3H), 0.98 (t, J=7.8 Hz, 9H), 0.64 (q, J=7.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 153.9, 149.8, 140.9, 139.8, 136.5, 135.0, 130.9, 122.4, 115.2, 87.2, 51.8, 39.2, 18.4, 13.4, 7.2, 5.5; HRMS calcd for C20H31NOSi+H+ 330.2253 found 330.2258 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7]O.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[Br:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][C:15]#[N:17]
Reactant: COCOc1cc(Cl)c(Br)cc1CO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COCOc1cc(Cl)c(Br)cc1CC#N
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 5-bromo-4-chloro-2-methoxymethoxybenzyl alcohol (137.9 g) and triethylamine (105 ml) in dichloromethane (500 ml) was added at 0° C. methanesulfonyl chloride (45.5 ml) over a period of 30 minutes. The mixture was stirred overnight (13 hours), while warming up to room temperature. The reaction mixture was poured into water, to which was added dichloromethane for extraction. The extract solution was dried (anhydrous magnesium sulfate) and concentrated. To a suspension of the concentrate and sodium cyanide (51.4 g) in dichloromethane (40 ml) was added dropwise at 0° C. DMSO (300 ml). The mixture was then stirred for 3 hours at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried (anhydrous magnesium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-bromo-4-chloro-2-methoxymethoxybenzyl cyanide (86.4 g) (Compound B-35). The physical properties are shown in [Table 6].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCCCCC.O.P(Cl)(C(C)(C)C)C(C)(C)C>[C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccccn1
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 24 mg (0.044 mmol) of (t-Bu)2PCl)2PdCl2, 1.0 (8.8 mmol) of 2-chloropyridine, 1.3 g (10.66 mmol) of Ph—B(OH)2, 3.7 g (26.77 mmol) of K2CO3 in 5 mL of THF. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 220 mL of hexane and 150 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (100 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.3 g (95% yield) of 2-phenylpyridine.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].C1COCC1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>[OH-].[Na+].O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][CH:2]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:3]([OH:5])=[O:4])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC(CC1CCCCC1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC1CCCCC1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(RS)-phenylalanine (500.2 mg) was dissolved in H2O (50 ml) and 2N NaOH (1.5 ml). Rh/Al2O3 catalyst (500.5 mg) was added, and the whole was stirred overnight under a hydrogen atmosphere at atmospheric pressure. After the reaction was completed, Rh/Al2O3 was separated by filtration. The filtrate was concentrated to give crude (RS)-2-amino-3-cyclohexylpropanoic acid. Then, the crude (RS)-2-amino-3-cyclohexylpropanoic acid was dissolved in 2N NaOH (15.08 ml). THF (15 ml) and then 4-chlorobenzenesulfonyl chloride (3.196 g) were added, and the whole was stirred at room temperature overnight under argon. The reaction mixture was diluted with water, washed with ethyl acetate, acidified with 2N HCl and extracted 3 times with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 80 g, ethyl acetate) and then by preparative TLC to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanoic acid (200.9 mg).
Reaction SMILES: C(O)(=O)C.C(=O)([O-])O.[K+].[C:10]([NH:14][C:15]([C@@H:17]1[CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][NH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CS([O:31][C@@H:32]1[C@@H:38]([NH:39][C:40](=[O:52])[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47]C(=O)C)[C:42]=2[CH3:51])[CH2:37]OC(C)(C)O[CH2:33]1)(=O)=O>>[C:10]([NH:14][C:15]([C@@H:17]1[CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][N:18]1[CH2:33][C@H:32]([C@@H:38]1[CH2:37][O:52][C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([OH:47])[C:42]=2[CH3:51])=[N:39]1)[OH:31])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: CC(=O)Oc1cccc(C(=O)N[C@H]2COC(C)(C)OC[C@@H]2OS(C)(=O)=O)c1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1c(O)cccc1C1=N[C@H]([C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)CO1
Temperature: 45 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
Acetic acid (14.0 ml, 245 mmol) was added to the mixture obtained in Example 8 at not more than 10° C. to make the mixture acidic, and potassium hydrogencarbonate (25.0 g, 250 mmol) and (3S, 4aS, 8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [12], 13.7 g, 57.6 mmol) were successively added. The mixture was stirred at 45° C. for 6 hours to give a pale yellow suspension. The suspension was concentrated to 1/5 and water (340 ml) was added. The suspension was stirred for one hour at room temperature. The resulting crystals were collected by filtration and washed successively with water (200 ml) and butyl acetate (340 ml). The crystals were dried under reduced pressure at 60° C. to give colorless crystals of (3S, 4aS, 8aS)-2-{(2R)-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [13], 17.3 g, yield 46%, from compound [9]), melting point 240° C.
Reaction SMILES: [N:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[C:2]=[S:3].CO[CH:11](OC)[CH2:12][NH2:13]>C1(C)C=CC=CC=1>[S:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[N:1]1[CH:11]=[CH:12][NH:13][C:2]1=[S:3]
Reactant: S=C=Nc1cccs1
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Product: S=c1[nH]ccn1-c1cccs1

Procedure:
A mixture of 2-isothiocyanatothiophene (16.9 g, 0.12 mol) and aminoacetaldehyde dimethyl acetal (12.6 g, 0.12 mol) in 200 ml toluene is refluxed for 2 hours. After removal of the toluene, the residue is dissolved in 200 ml ethanol and 45 ml conc. HCl added. After the reaction is refluxed for 5 hours, it is poured onto ice. The product is collected and purified by recrystallization.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[C:10]=2[C:11]=1[CH3:12].[NH3:15]>>[CH3:1][C:2]1[C:3](=[O:4])[NH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[C:10]=2[C:11]=1[CH3:12]
Reactant: N
Reactant: Cc1c2c(oc(=O)c1C)CCCC2=O
Product: Cc1c2c([nH]c(=O)c1C)CCCC2=O

Procedure:
Prepared from 3,4-dimethyl-5,6,7,8-tetrahydro-cumarin- 5-one (melting point: 109°-111° C., prepared from methyl 2methylacetoacetate and cyclohexan-1,3-dione) and methanolic ammonia for one hour in an autoclave at 150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Mg]Cl.CN(C)P(N(C)C)(N(C)C)=O.FC(F)(F)S(N(C1C=CC(Cl)=CN=1)S(C(F)(F)F)(=O)=O)(=O)=O>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH:13]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1C=CC(=O)CC1
Agent: O=S(=O)(N(c1ccc(Cl)cn1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A solution of 4.0 gm (20.28 mMol) 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydropyridin-4-one and 4.21 gm (20.48 mMol) copper(I) bromide-dimethylsulfide complex in 160 mL tetrahydrofuran was cooled to −780C. To this solution was added 7.43 mL (22.31 mMol) methyl magnesium chloride (3.0 M in tetrahydro-furan). After stirring for 1 hour at −78° C. an additional equivalent of methyl magnesium chloride was added and stirring continued for an additional 30 minutes. The reaction mixture was then treated with 10 mL hexamethylphosphoramide followed by the addition of a solution of 15.93 gm (40.56 mMol) 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in 50 mL tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. The reaction mixture was then diluted with 1.5 L diethyl ether and was washed sequentially with 2×500 mL saturated aqueous oxalic acid, 500 mL water, 2×500 mL saturated aqueous sodium bicarbonate, and 500 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was suspended in hexanes and then filtered. The filtrate was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with a gradient of hexane containing 0-50% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 1.92 gm of the title compound as an oil that gradually formed a crystalline mass.