Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=3)[C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Reactant: COc1cccc(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1cccc(OC)c1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-allyloxy-8acetyl -3-methylflavone (2.5 g, 0.0075 mol) and 3-methoxy-benzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.4 g of product m.p. 90-92° C., 1H-NMR (CDCl3)δ:2.20 (s, 3H); 3.84 (s, 3H); 4.74 (d, 2H, J=5.1 Hz); 5.1-5.3 (m, 2H); 5.91-6.02 (m, 1H); 6.96-7.18 (m, 4H); 7.31 (d, 1H, J=16 Hz); 7.32-7.35 (m, 1H); 7.36-7.43 (m, 3H); 7.55-7.59 (m, 2H); 8.34 (d, 1H, J=8.9Hz).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH3:3].[H-].[Na+].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>CN(C=O)C>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:14][CH2:13]3)=[CH:21][CH:20]=1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC1CCc2cc(OCc3ccc(Br)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
2-(N,N-Dimethylamino)methyl-6-hydroxytetralin (5.0 g; obtained in Reference Example 16) was dissolved in DMF (130 ml), to which was added 60% oily sodium hydride (1.46 g) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 1 hour. This was again cooled to 0° C., to which was added a DMF solution (20 ml) of 4-bromobenzyl bromide (10.0 g). The reaction mixture was stirred at room temperature for 2 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain the entitled compound (3.4 g).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([C:17](SC)=[S:18])[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2=[O:16])[CH:5]=1.C>C(O)C.C(C(C)=O)C.C(OC(C)C)(C)C>[CH2:1]([NH:3][C:17]([C:10]1([C:6]2[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][S:11]1=[O:16])=[S:18])[CH3:2]
Reactant: CSC(=S)C1(c2cccnc2)CCCCS1=O
Reactant: CCN
Solvent: CCC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CCNC(=S)C1(c2cccnc2)CCCCS1=O
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
Ethylamine (34 g) is added dropwise, in the course of 5 minutes, to a solution of methyl 2-(pyridin-3-yl)tetrahydrothiopyran-2-carbodithioate 1-oxide (10.7 g) in ethanol (120 cc), kept at between 20° and 25° C. The solution is then stirred for 1 hour 30 minutes at the same temperature and then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The product obtained (12 g) is chromatographed on neutral silica gel (0.040-0.063 mm; 145 g) contained in a column of diameter 4 cm, under a pressure of 40 kPa. The column is eluted with a mixture of ethyl acetate and methanol (90/10 by volume), one 300 cc fraction and thirty-two 120 cc fractions being collected. Fractions 16 to 33 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The product obtained (4 g) is dissolved in a boiling mixture of methyl ethyl ketone (9 cc) and diisopropyl ether (2 cc); after cooling, the solution is kept at a temperature of about 0° C. for 2 hours. The resulting crystals are filtered off, washed with methyl ethyl ketone (3 cc) and with diisopropyl ether (0.5 cc) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product obtained (2.6 g), to which 1.2 g prepared under the same conditions in an earlier operation have been added, is dissolved in boiling methyl ethyl ketone (25 cc); the solution is treated with decolourising charcoal (0.2 g) and filtered hot and the filtrate is cooled and kept at a temperature of about 0° C. for 1 hour 30 minutes. The resulting crystals are filtered off, washed with methyl ethyl ketone (6 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. This gives the A form of N-ethyl-2-(pyridin-3-yl)tetrahydrothiopyran-2-carbothioamide 1-oxide (3 g) melting initially at about 169° C. and then, after resolidification, at 183° C. [Rf=0.30; chromatography on a thin layer of silica gel; solvent: ethyl acetate/methanol (80/20 by volume)].
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.Cl>CN(C=O)C>[F:13][C:6]1[CH:5]=[C:4]([B:1]([OH:2])[OH:3])[CH:12]=[CH:11][C:7]=1[C:8]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:10]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccc(B(O)O)cc1F)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a solution of 4-borono-2-fluorobenzoic acid (1.0 g, 5.43 mmol) and HATU (2.0 g, 5.43 mmol) in DMF (20.0 mL) was added morpholine (0.9 g, 10.87 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into ice cold water, acidified with 1N HCl, extracted with EtOAc (2×50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford 1.2 g of crude compound as a colourless gum. Crude compound was directly used for the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9](C)([O-:11])[CH3:10].[Na+].[C:14](P(C(C)(C)C)C(C)(C)C)(C)([CH3:16])[CH3:15]>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:15]1[C:10]2[NH:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:11][C:9]=2[CH:8]=[CH:16][CH:14]=1
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: CC(C)(C)[O-]
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)Nc1ccccc1O2
Temperature: 60 °C

Procedure:
17 g (41 mmol) of Compound b, 7.6 g (82 mmol) of aniline, 7.4 g (77 mmol) of sodium tert-butoxide, 0.61 g (1.1 mmol) of Pd2(dba)3 [(tris(dibenzylidine acetone) dipalladium(0))], and 0.22 g (1.1 mmol) of tri(tert-butyl)phosphine were dissolved in 200 mL of xylene, and then refluxed at 60° C. for 1 hour.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:19][CH2:20][C:21](O)=[O:22].N>O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20](=[O:19])[CH2:21][OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(O)CO
Agent: N
Solvent: O
Product: O=C(CO)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 94.8 %

Procedure:
1.59 g of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine and 536 mg of hydroxyacetic acid were heated at 200° C. for 2 hours. The reaction mixture was cooled, and water was added. The mixture was alkalized with aqueous ammonia, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to afford 1.86 g of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)=[N:8][CH:9]=1.[Cl:18][C:19]1[C:20]([C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])=[N:21][CH:22]=[CH:23][N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Cl:18][C:19]1[C:20]([C:25]([CH3:30])([CH3:29])[C:26]([NH:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][N:8]=3)[CH2:12][CH2:13]2)=[O:27])=[N:21][CH:22]=[CH:23][N:24]=1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Reactant: Cc1ccc(N[C@H]2CC[C@H](N)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N[C@H]2CC[C@H](NC(=O)C(C)(C)c3nccnc3Cl)CC2)nc1
Temperature: 25 °C

Procedure:
To a round bottom flask was added trans-N1-(5-methylpyridin-2-yl)cyclohexane-1,4-diamine dihydrochloride (intermediate 31, 0.2108 g, 0.758 mmol), 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (intermediate 29, 0.182 g, 0.909 mmol), HATU (0.375 g, 0.985 mmol), and triethylamine (0.422 ml, 3.03 mmol) in dichloromethane (1.515 ml) to stir at room temperature. After 4 hours the solvent was evaporated off. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 0% to 5% methanol in dichloromethane, to provide 2-(3-chloropyrazin-2-yl)-2-methyl-N-(trans-4-((5-methylpyridin-2-yl)amino)cyclohexyl)propanamide (0.2148 g, 0.554 mmol, 73.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH3:14])[CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:13][CH3:14])[CH2:9][CH2:10][C:11]([OH:17])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: COC(CCCO)c1ccc(Cl)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(CCC(=O)O)c1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chloro-phenyl)-4-methoxy-butan-1-ol (120.0 mg, 0.56 mmol) in 6 mL acetone was added dropwise at room temperature 0.6 mL of Jones reagent. After stirring an additional 30 min water was added and the mixture extracted with DCM (3×20 mL). The combined DCM layers were washed with water (2×10 mL) and dried over Na2SO4. The solvent was evaporated under reduce pressure and the crude product was used for the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[NH:29][C:28](=[O:30])[C@@H:27]([NH:31]C(OC(C)(C)C)=O)[CH2:26][C:25]2[CH:39]=[C:21]([CH:22]=[CH:23][C:24]=2[OH:40])[C:20]2=[CH:41][C:16](=[C:17]([OH:42])[CH:18]=[CH:19]2)[CH2:15][C@@H:14]([C:43]([NH:45][CH2:46][CH2:47][CH2:48][C@H:49]([NH2:57])[CH2:50][C:51]([NH:53][CH2:54][CH2:55][NH2:56])=[O:52])=[O:44])[NH:13][C:12]1=[O:58])(C)(C)C.[H][H].[Cl-:62].O1CCOCC1>>[ClH:62].[ClH:62].[ClH:62].[ClH:62].[NH2:31][C@H:27]1[CH2:26][C:25]2[CH:39]=[C:21]([CH:22]=[CH:23][C:24]=2[OH:40])[C:20]2=[CH:41][C:16](=[C:17]([OH:42])[CH:18]=[CH:19]2)[CH2:15][C@@H:14]([C:43]([NH:45][CH2:46][CH2:47][CH2:48][C@H:49]([NH2:57])[CH2:50][C:51]([NH:53][CH2:54][CH2:55][NH2:56])=[O:52])=[O:44])[NH:13][C:12](=[O:58])[C@H:11]([CH2:10][CH2:9][CH2:8][NH2:7])[NH:29][C:28]1=[O:30]
Reactant: [Cl-]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)NCCC[C@H](N)CC(=O)NCCN)NC1=O
Solvent: C1COCCO1
Product: Cl
Product: NCCC[C@@H]1NC(=O)[C@@H](N)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)NCCC[C@H](N)CC(=O)NCCN)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8 mg (0.010 mmol) of tert-butyl{3-[(8S,11S,14S)-8-[({(4S)-4-amino-6-[(2-aminoethyl)amino]-6-oxohexyl}amino)carbonyl]-14-[(tert-butoxycarbonyl)amino]-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-11-yl]propyl}carbamate bis(hydroacetate) (Example 206A) are added into 0.4 ml of a 4N solution of hydrogen in dioxane chloride and stirred at RT for 30 min. The reaction solution is concentrated, coevaporated with dichloromethane several times and dried under high vacuum.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N(OC(C)(C)C)=O.[ClH:19]>C(#N)C.[Cu](Cl)Cl>[Cl:19][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Fc1ccc2nc(Cl)sc2c1
Temperature: 65 °C
Yield: 83 %

Procedure:
To a round bottomed flask was added 2-amino-6-fluorobenzothiazole (1.0017 g, 5.96 mmol, Sigma-Aldrich Chemical Company, Inc.), copper (II) chloride (1.201 g, 8.93 mmol, Sigma-Aldrich Chemical Company, Inc.), and tert-butyl nitrite (1.063 ml, 8.93 mmol, Acros Organics) in ACN and was heated to 65° C. for 2 hours. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (0.9249 g, 4.93 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm s 7.45 (td, J=9.10, 2.74 Hz, 1 H) 7.97-8.07 (m, 2 H)
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:15][C:14]([C:12]1[CH:13]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:7]=2)[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(-c2nc(CCl)no2)cc(C(C)(C)C)c1O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nc(CN3CCCC3)no2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.5 g (0.002 mole) of 4-[3-(chloromethyl) -1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol and 0.4 g (0.006 mole) of pyrrolidine in DMF (10 ml) is stirred at room temperature for three hours. The mixture is poured into ice water (50 ml) and extracted with ethyl acetate (3×25 ml). The organic phase is washed with water (3×40 ml), dried (anhydrous magnesium sulfate), and evaporated, leaving an oil. Purification by flash chromatography (silica gel, ethyl acetate/hexane elution) yields 0.4 g (73%) of analytically pure 2,6-bis(1,1-dimethylethyl) -4-[3-(1-pyrrolidinylmethyl)-1,2,4-oxadiazol5-yl]phenol, mp 100°-102° C.
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)C[CH2:2]1.[OH:12][CH:13]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[CH2:28][CH2:27][C@@H:26]2[CH2:31][CH2:32][CH2:33][C:34]2[S:38][C:37]([C:39]([OH:41])=[O:40])=[CH:36][CH:35]=2)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].IC(C)C>CC(C)=O>[CH:1]([O:40][C:39]([C:37]1[S:38][C:34]([CH2:33][CH2:32][CH2:31][C@H:26]2[CH2:27][CH2:28][C:29](=[O:30])[N:25]2[C:22]2[CH:21]=[CH:20][C:19]([CH:13]([OH:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=2)=[CH:35][CH:36]=1)=[O:41])([CH3:11])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Solvent: CC(C)=O
Solvent: CC(C)I
Product: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OC(C)C)s2)cc1
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
DBU (5.2 μL, 0.035 mmol) was added to a solution of acid 43 (7.5 mg, 0.017 mmol) in acetone (0.1 mL) at rt under nitrogen. After 10 min, 2-iodopropane (35 μL, 0.35 mmol) was added. After 21 h at rt, the reaction was quenched with 0.01 N HCl (3 mL) and extracted with EtOAc (3×4 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica (CH2Cl2→1% MeOH CH2Cl2) afforded 4.6 mg (53%) of the title compound (44).
Reaction SMILES: O.[N-:2]=[N+:3]=[N-:4].[Na+].CS(O[CH2:11][C:12]1[O:13][CH2:14][CH2:15][CH2:16][CH:17]=1)(=O)=O>CN(C)C=O>[N:2]([CH2:11][C:12]1[O:13][CH2:14][CH2:15][CH2:16][CH:17]=1)=[N+:3]=[N-:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1=CCCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1=CCCCO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Water (35 mL) and sodium azide (15.1 g, 232 mmol) were added to a solution of the crude (5,6-dihydro-4H-pyran-2-yl)methyl methanesulfonate (about 193 mmol) in N,N-dimethylformamide (350 mL), and the mixture was stirred at room temperature for 20 hours. Water (300 mL) was added to the reaction solution, followed by extraction with ethyl acetate (1.5 L). The resulting organic layer was washed with water (3×200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to about 300 mL. The resulting crude title compound solution was used for the next reaction without purification.
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18].C([BH3-])#N.[Na+]>C(O)C.O>[CH2:6]([O:5][C:3]([CH:2]([NH:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 65.1 %

Procedure:
Ethyl 2-oxo-4-phenylbutyrate (1.03 g) and L-alanyl-L-proline (0.19 g) are dissolved in a 1:1 ethanol-water solvent. A solution of sodium cyanoborohydride (0.19 g) in ethanol-water is added dropwise at room temperature over the course of two hours. When reaction is complete, the product is absorbed on strong acid ion-exchange resin and eluted with 2% pyridine in water. The product-rich cuts are freeze dried to give 0.25 g of crude N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline. The mass spectrum shows a molecular ion at 448 m/e for the monosilylated species. Chromatography affords the desired isomer.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH2:16][NH:15][CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9].Cl[C:18]1[C:19]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:31]=3[S:39][CH3:40])[C:20]=2[N:21]=[C:22]([CH3:24])[N:23]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[C:8]([C:11]1[CH2:16][N:15]([C:18]2[C:19]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[CH:32][C:31]=4[S:39][CH3:40])[C:20]=3[N:21]=[C:22]([CH3:24])[N:23]=2)[CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9]
Reactant: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(Cl)nc(C)nc21
Reactant: NC(=O)C1=CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(N3CCC=C(C(N)=O)C3)nc(C)nc21
Yield: 26.7 %

Procedure:
In 4 ml of ethanol, 0.27 g of 5-carbamoyl-1,2,3,6-tetrahydropyridine trifluoroacetate and 0.36 g of 4-chloro-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine were dissolved, and subsequently, 0.39 g of diisopropylethylamine was added thereto. The reaction mixture was heated under reflux for 8.5 hours, and subsequently, a saturated aqueous solution of sodium hydrogencarbonate was poured thereinto. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=60:1), followed by crystallization from a mixed solvent of ethyl acetate-diethyl ether to yield 0.12 g of 4-(5-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[C:8]#N.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+].[OH2:19]>>[Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[C:8]([OH:11])=[O:19]
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(Cl)nsc1Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)c1c(Cl)nsc1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Into a 500-mL round-bottom flask, was placed dichloro-1,2-thiazole-4-carbonitrile (36 g, 201.09 mmol, 1.00 equiv), Conc. sulfuric acid (100 mL). The resulting solution was stirred for 2 h at 100° C. in an oil bath. This was followed by the addition of a solution of NaNO2 (15 g, 217.39 mmol, 1.08 equiv) in water (100 mL) dropwise with stirring at 0° C. The resulting solution was allowed to react, with stirring, for overnight while the temperature was maintained at 50° C. in an oil bath. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 5×500 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 30 g (75%) of dichloro-1,2-thiazole-4-carboxylic acid as red oil. Mass spectrum (ESI, m/z): Calcd. for C4HCl2NO2S, 197.1 (M+H). found 197.1.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4](Cl)=[N:5][OH:6].[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[K+]>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:9])[C:3]([C:4]1[CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:6][N:5]=1)=[O:8]
Reactant: C=Cc1ccccc1
Reactant: CN(C)C(=O)C(Cl)=NO
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C1=NOC(c2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(dimethylamino)-N-hydroxy-2-oxoethanimidoyl chloride (prepared according to the procedure of E. Raleigh, U.S. Pat. No. 3,557,089) (6.0 g, 40 mmol) and styrene (6.0 g, 60 mmol) in toluene (15 mL) was added a solution of potassium hydrogen carbonate (5.0 g, 50 mmol) in water (25 mL) over 1 h, while keeping the reaction temperature between 7 and 10° C. The reaction mixture was diluted with 10 mL of toluene and stirred for an additional 10 minutes. The organic layer was separated and washed with water. The organic layer was concentrated under reduced pressure until no styrene remained to give 8.7 g of the title compound as a light yellow oil. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: C([Li])CCC.[CH2:6]([CH:10]([CH2:14]C)[C:11]([OH:13])=[O:12])C(C)C.[CH:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)([CH3:18])[CH3:17].Cl>O1CCCC1.C(NC(C)C)(C)C>[CH:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:10]([CH3:14])([CH3:6])[C:11]([OH:13])=[O:12])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CCC(CC(C)C)C(=O)O
Reactant: CC(C)c1ccc(CCl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)c1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
in tetrahydrofuran (40 ml) was dissolved in diisopropylamine (3.08 ml) and to the mixture was added n-butyl lithium (13.8 ml; 1.6 M hexane solution) at −78° C. and thereto was added isobutylbutyric acid (0.93 ml) dropwise and the mixture was stirred for 1 hour at 30° C. To the reaction mixture was added a solution of 4-isopropylbenzyl chloride (2.19 g) in tetrahydrofuran (10 ml) at −78° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to cool hydrochloric acid and was extracted with ethyl acetate. The extract was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (1.73 g) having the following physical data.