Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16](/[N:18]=[CH:19]/[N:20](C)C)=O)=[CH:10]3)=[CH:4][CH:3]=1.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>CC(O)=O>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:27]([CH:24]([CH3:26])[CH3:25])[N:20]=[CH:19][N:18]=2)=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CN(C)/C=N/C(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C
Yield: 78.8 %

Procedure:
To a solution of 13-bromo-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (2.2 g, 6.1 mmol) in AcOH (20 mL) was added isopropylhydrazine hydrochloride (0.73 g, 6.6 mmol). The mixture was heated at 100° C. for 1 h. Most of the solvent was removed and water (50 mL) was added. The solid was collected by filtration, washed with water, and dried in vacuo to afford the title compound (1.8 g, 74% yield) as a yellow solid. LCMS m/z [M+H]+ 376.1.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
Triethylamine (35.95 mL, 257.9 mmol) was added to a suspension of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (49.6 g, 172 mmol) in dichloromethane (500 mL). 1-Amino-2-methylpropan-2-ol (16.86 g, 189 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. The residue was triturated with water and stirred for 1 hour. The precipitated solid was isolated by filtration, washed with water, and dried. This material was suspended in diethyl ether (400 mL), sonicated, isolated by filtration, and then dried in a vacuum oven at 40° C. for 16 hours to provide 58.1 g of 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid, mp 189-190° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(CC)CC)C>ClCCl.O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([O:7][C:6]2[CH:22]=[CH:23][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCCN3)cc2)cc1
Reactant: COC(=O)CCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 33.8 %

Procedure:
A solution of (S)-2-[4-(4-chloro-phenoxy)-phenoxymethyl]-piperidine hydrochloride (218 mg, 0.615 mmol), methyl 4-bromobutyrate (139 mg, 0.769 mmol), and triethylamine (124 mg, 1.23 mmol) in dichloromethane (2.5 mL) was heated for 18 h at 30° C. The mixture was diluted with 5 mls of water and extracted with dichloromethane (8 mL). The aqueous layer was re-extracted with ethyl acetate (8 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (87 mg, 34%): 1H NMR (400 MHz, CDCl3) δ 1.52-1.86 (m, 6H), 2.11-2.12 (m, 1H), 2.21-2.2 (m, 1H), 2.27-2.33 (m, 3H), 2.49-2.56 (m, 1H), 2.66-2.70 (m, 1H), 2.74-2.81 (m, 1H), 2.86-2.91 (m, 1H) 3.64 (s, 3H), 3.91-3.94 (dd, 1H J1=4.4 Hz, J2=10 Hz), 4.0-4.03 (dd, 1H J1=4.4 Hz, J2=10 Hz) 6.86-6.89 (m, 4H), 6.94-6.96 (m, 2H), 7.23-7.25 (m, 2H); MS
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:18])([F:17])[C:9]([F:16])([F:15])[C:10]([O:12]CC)=O.[CH3:19][C:20]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[O:21].C(O)(=O)C>CCOCC.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:18][C:8]([F:7])([F:17])[C:9]([F:15])([F:16])[C:10](=[O:12])[CH2:19][C:20](=[O:21])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CC(=O)C(F)(F)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: O=C(CC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of potassium t-butoxide (44.8 g., 0.4 mole) in dry ether (400 ml.) is added ethyl pentafluoropropionate (76.8 g., 0.4 mole) over a period of about 15 minutes. Most of the solid dissolves. A solution of pentafluoroethyl methyl ketone (64.8 g., 0.4 mole) in dry ether (60 ml.) is added slowly, and after stirring the mixture for 2 hours at room temperature, it is allowed to stand overnight. A solution of glacial acetic acid (27.2 ml.) in water (120 ml.) is added with stirring and external cooling (ice-bath). Then a warm solution of copper acetate (56.0 g., 0.28 mole) in water (532 ml.) is added slowly with stirring and cooling. The ether is distilled off, and the copper salt of the product is collected by filtration, washed with water, drained thoroughly, and then washed with petroleum ether. The copper derivative is suspended in ether (200 ml.) and decomposed by treatment with 15% sulphuric acid (450 ml.). The aqueous layer is separated and extracted with more ether (3 × 50 ml.). The combined ethereal extract is dried, first over anhydrous sodium sulphate and then over anhydrous calcium sulphate. Evaporation of the ether gives the product which is purified by fractionational distillation at atmospheric pressure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][N:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28]([OH:30])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:31]([N:34](CC)[CH:35](C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CNC.C1COCC1>CN(C=O)C.CO>[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][N:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28]([N:34]([CH3:35])[CH3:31])=[O:30])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(C(=O)N(C)C)n3Cc3ccccc3)n12
Reaction time: 0.03 h

Procedure:
To a solution of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid trifluoroacetate (0.015 g, 0.036 mmol, from Example 83, Step 5) in DMF (0.3 mL) was added N,N-diisopropylethylamine (0.058 mL, 0.33 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.048 g, 0.12 mmol). After stirring for 2 minutes, 2.0 M dimethylamine in THF (0.14 mL, 0.28 mmol, Aldrich) was added. After 15 minutes reaction time, the reaction was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (1.2 mg, 10%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CC1(C)C(C)(C)OB([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[CH:27][CH:26]=2)=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: CC1(C)OB(c2ccc(-c3cccs3)c3ccccc23)OC1(C)C
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1c2ccccc2c(-c2ccc(-c3cccs3)c3ccccc23)c2ccccc12
Temperature: 90 °C
Yield: 53.2 %

Procedure:
A mixture of 13.4 g (40 mmol) of 9,10-dibromoanthracene, 20.1 g (60 mmol) of 4,4,5,5-tetramethyl-2-(4-(thiophen-2-yl)naphthalen-1-yl)-1,3,2-dioxaborolane, 0.46 g (0.4 mmol) of tetrakis(triphenylphosphine)palladium, 30 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product 9.9 g (53%) as a yellow solid.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].Cl.N>O.CO>[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNCCO
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Nc1c(N=O)cnn1CCO
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a flask having an inner volume of 50 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 4.59 g (30 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 94.3% by weight synthesized in the same manner as in Example 1, 2.98 g (31.5 mmol) of 2-hydroxyethylhydrazine with a purity of 80.5% by weight, 7.8 ml of methanol and 4.5 ml (54 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for 3 hours. After completion of the reaction, 7 ml of water was added to the mixture and the resulting mixture was cooled up to 10° C. Then, 3.5 ml (58 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. The precipitated crystals were collected by filtration, and then, the crystals were washed with 2.5 ml of cold water and 2.5 ml of cold methanol, and dried under reduced pressure to obtain 3.40 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole (Isolation yield: 69.7%) as reddish orange crystals with a purity of 96.0% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=[C:8]([C:29]([O:31]C)=[O:30])[O:7][C@H:6]1[C:33]([O-:35])=O)(=[O:3])[CH3:2].Cl.[C:37]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH:45][CH2:46][CH2:47][CH3:48])=[CH:39][CH:38]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:4][C@H:5]1[C@H:6]([C:33](=[O:35])[N:45]([CH2:44][CH2:43][C:40]2[CH:39]=[CH:38][C:37]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[CH:42][CH:41]=2)[CH2:46][CH2:47][CH3:48])[O:7][C:8]([C:29]([OH:31])=[O:30])=[CH:9][C@@H:10]1[OH:11])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H](NC(C)=O)[C@H](C(=O)[O-])O1
Reactant: CCCNCCc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](O)[C@H]1NC(C)=O
Temperature: 23 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a solution of (2R,3R,4S)-3-acetylamino-4-(tert-butyldiphenylsilanyloxy)-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid, 6-methyl ester (2.0 g), (2-biphenyl-4-yl-ethyl)propylamine hydrochloride (1.33 g) and diisopropyl ethylamine (2.52 ml) in anhydrous dimethylformamide (5 ml) was added 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (1.55 g). The reaction was stirred at 23° C. for 24 hours then diluted with ethyl acetate (200 ml) and washed with water (2×200 ml), dilute hydrochloric acid (100 ml), saturated sodium bicarbonate solution (100 ml) and brine (100 ml). The organic phase was dried over anhydrous magnesium sulphate and the solvent was removed in vacuo and the residue was chromatographed over silica (Merck 9385, 20 g) using medium pressure (ca 4 psi) and cyclohexane/ethyl acetate (10:1 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white solid (1.6 g). 1H NMR (250 MHz, D6 -DMSO rotamers) 8.16+8.12 (1H,2×d, J=10 Hz), 7.64 (8H, m), 7.53-7.30 (11H, m), 5.50 (1H, m), 5.11 (1H, m), 4.54+4.40 (1H, 2×m), 4.26 (1H, m), 3.71+3.65 (3H, 2×s), 3.6-3.1 (4H, m), 2.92 (1H, m), 2.82 (1H, m), 1.81+1.79 (3H, 2×s), 1.62 (1H, m), 1.52 (1H, m), 1.02 (9H, s), 0.91+0.82 (3H, 2×t, J=7 Hz). Mass analysis: C43H50N2O6Si. Required: C, 71.84; H, 7.01; N, 3.90. Found: C, 71.54; H, 7.33; N, 3.88.
Reaction SMILES: CO.[CH3:3][O:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])O[C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:6].[CH2:22]([NH2:24])[CH3:23].Cl>O.C(O)(=O)C>[CH2:22]([N:24]1[C:10]([CH3:14])=[CH:11][C:12](=[O:13])[C:7]([C:5]([O:4][CH3:3])=[O:6])=[C:8]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH3:23]
Reactant: CCN
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)oc(C)cc1=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(C)cc(=O)c(C(=O)OC)c1-c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A 1000 ml flask is fitted with a magnetic stirring bar and a sidearm addition funnel. 500 mls of methanol, 30 mls of glacial acetic acid and 60 gms of 3-methoxycarbonyl-6-methyl-2-(4'-chlorophenyl)-4-pyrone are added. 120 mls of 70% aqueous ethylamine is placed in the addition funnel and added very slowly (4 hr. addition time). 50 mls of water is then added followed by 100 mls of concentrated HCl (cooling required). The reaction mixture is allowed to stand undisturbed for 30 minutes. The bulk of the methanol is then removed in vacuo leaving 46.1 gms of methyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate. mp (methylene chloride/ether)=217°-219° C.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7](=[N:9][OH:10])[CH3:8].[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=O)=[CH:14][CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[O:10][N:9]=[C:7]([CH3:8])[CH:6]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC(C)=NO
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Br)cc2)on1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of n-BuLi (81 ml of a 1.6M solution in hexanes) was added to a solution of acetone oxime (4.85 g) in THF (100 ml) at 0° C. The reaction mixture was allowed to warm to rt over 1 h. A solution of methyl 4-bromobenzoate (9.4 g) in THF (30 ml) was then added to the reaction mixture and allowed to stir for 24 h. Water (50 ml) was added to the reaction, the organics were extracted and evaporated to give a brown oil, which was further evaporated from toluene (2×25 ml). The crude product was purified by column chromatography (silica gel, 10-25% gradient of EtOAc in hexane) to give the title compound (D39) as a pale yellow solid (5.4 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(O)(=O)C.C(O[C:27]1(O[Si](C)(C)C)[CH2:29][CH2:28]1)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[CH:27]2[CH2:29][CH2:28]2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc(NC(=O)[C@@H]2CCCCN2)s1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nnc(NC(=O)[C@@H]2CCCCN2C2CC2)s1

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-1,3,4-thiadiazol-2-yl)-amide; hydrochloride (125 mg; 0.41 mmol) in methanol (3 mL) is added acetic acid (0.235 mL; 4.1 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.48 mL; 2.4 mmol) and sodium cyanoborohydride (116.25 mg; 1.85 mmol). The reaction mixture is heated at reflux for 5 hours. After cooling, the mixture is diluted with ethyl acetate and washed with saturated NaHCO3 aqueous solution then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC affords the title compound, m/z 309 [M+H+].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].Cl.[OH-].[K+].[C:11](=O)(OC(Cl)(Cl)Cl)[O:12]C(Cl)(Cl)Cl>O.CCOC(C)=O.C1COCC1>[O:7]1[C@@H:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[NH:1][C:11]1=[O:12]
Reactant: N[C@H]1CCC[C@H]1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1N[C@H]2CCC[C@H]2O1
Temperature: 0 °C
Yield: 24.2 %

Procedure:
To a solution of (1R,2S)-2-aminocyclopentanol (1.0 g, 9.9 mmol) as the HCl salt in water (50 mL) was added potassium hydroxide (3.9 g, 69 mmol) and the slurry stirred until all the material was in solute ion. To the reaction was added THF (100 mL) and the reaction was cooled to 0° C., followed by bis(trichloromethyl) carbonate (2.9 g, 9.9 mmol) as a solid and the reaction stirred at 0° C. for 2 hours. The reaction was poured into EtOAc and the layers were separated. The organic layer was washed with 1N HCl, 1N NaOH and brine, dried over MgSO4 and concentrated in vacuo. The material was purified by silica gel chromatography using 20% EtOAc/DCM as the eluent to yield (3aS,6aR)-hexahydro-2H-cyclopenta[d]oxazol-2-one (0.30 g, 2.4 mmol, 24% yield).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([CH2:7]COC(=O)[O-])=[CH:3][CH:2]=1.[S].N1C2C(=CC=CC=2)C=CC=1.[O:25]1CCCC1>[Pd]>[CH3:13][C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[O:25])=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCOC(=O)[O-])cc1
Reactant: C1CCOC1
Agent: [Pd]
Agent: [S]
Solvent: c1ccc2ncccc2c1
Product: Cc1ccc(C=O)cc1
Yield: 88 %

Procedure:
To a solution containing 20.8 g (0.10 moles) of p-toluylethyl-carbonate in 300 ml of tetrahydrofuran there are added 10.4 g of Pd on BaSO4 10% and 0.1 cc of a solution of sulfur and quinoline 1:3000. Proceeding as in Example I, step (6), 10.5 g of p-methylbenzaldehyde (yield 88%) are obtained.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:16])([CH3:15])[C:4](=[N:13][OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:17][C:18]1[N:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[C:20]([OH:28])[N:19]=1.C(N(CC)CC)C>C(O)C>[NH2:17][C:18]1[N:19]=[C:20]([OH:28])[C:21]([N+:25]([O-:27])=[O:26])=[C:22]([NH:2][C:3]([CH3:16])([CH3:15])[C:4](=[N:13][OH:14])[CH2:5][O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:23]=1
Reactant: CC(C)(N)C(COc1ccccc1)=NO
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(COc1ccccc1)=NO
Yield: 16.1 %

Procedure:
A mixture of 3-amino-1-(p-chloro)-phenoxy-3-methylbutan-2-one oxime hydrochloride (IV) (5.58 g), 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine (III) (Hal = Cl) (3.81 g) and dry triethylamine (8.2 g) was heated to reflux in dry ethanol (240 ml) for 16 hours and filtered hot. The filtrate was reduced in volume and the solid so obtained was filtered off. Recrystallisation from ethanol gave the nitropyrimidine oxime (II) (1.17 g) as a pale yellow gelatinous solid, m.p. >250°C (decomp.).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh].C(OCC)(=O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C1=CNCCN1C(=O)C(F)(F)F
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: F[B-](F)(F)F
Solvent: C1=CCCC=CCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1CNCCN1C(=O)C(F)(F)F
Reaction time: 18 h
Yield: 99.3 %

Procedure:
250 g (8.95 mmol) of 1-trifluoroacetyl-1,4,5,6-tetra-hydropyrazine-2-carboxylic acid tert-butylamide, 7.5 mg (18 μmol) of bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate and 11.5 mg (21 μmol) of 1-[1(R)-(di-tert-butylphosphino)ethyl]-2(S)-(diphenylphosphino)ferrocene were placed in a 50 ml autoclave under argon (educt:catalyst=486). 20 ml of degassed ethyl acetate was added and hydrogenation was carried out for 18 hours at 90° C. under a hydrogen pressure of 13-10 bar. After distillation of the solvent, 2.50 g of the crude title compound was obtained in the form of a light yellow powder. After cleavage of the protecting groups, the enantioselectivity of the hydrogenation was determined by GC analysis, giving an ee of 47.2 percent. Other data concerning the title compound was:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:6][C:7]1[CH:14]=[C:13]([F:15])[C:10]([CH:11]=O)=[C:9]([Cl:16])[CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:16][C:9]1[CH:8]=[C:7]([OH:6])[CH:14]=[C:13]([F:15])[C:10]=1[CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1c(F)cc(O)cc1Cl
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cc(F)c(CN2CCCC2)c(Cl)c1
Yield: 69.8 %

Procedure:
Pyrrolidine (4.65 mL, 56 mmol) was added to a solution of intermediate 17, 4-hydroxy-2-chloro-6-fluorobenzaldehyde (7.5 g, 43 mmol) in dichloromethane (100 mL). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (13.71 g, 65 mmol) was added in portions under stirring. The reaction mixture was intensively stirred for 24 h at RT. Water (100 mL) and concentrated HCl were added to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×100 mL), then with EtOAc (100 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, the obtained crystals were separated by filtration, dried in vacuo, recrystallized from Et2O/hexane mixture (1:1) to give the title compound (7 g, 71%, 30 mmol). LCMS data: 231 and 230 (M+H)+ (calculated for C11H13ClFNO 229.7). 1H NMR data (DMSO-d6): 10.25 (br.s, 1H, OH), 6.66-6.70 (m, 1H, H—Ar), 6.54 (dd, 1H, J1=2.2 Hz, J2=11.3 Hz, H—Ar), 3.58 (d, 2H, J1=2.4 Hz, Ar—CH2); 2.38-2.46 (m, 4H), 1.58-1.68 (m, 4H).
Reaction SMILES: C(O)C.FC(F)(F)S(O[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=O)=O.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[N:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:10]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]1
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(c2ccncc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C

Procedure:
To a 1:1 (v/v) ethanol:toluene solution (0.18 M) of 1-(1,1-dimethylethyl) 3-ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (1 eq.) and 4-pyridinylboronic acid (1.1 eq.) was added sodium carbonate (2 M aq. solution, 2.6 eq.). The suspension was evacuated and back-filled with N2. Finally, tetrakis(triphenylphosphine)palladium(0) (0.04 eq.) was added in one rapid portion and the reaction suspension was heated at 80° C. for 18 h. The reaction was then quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 80:20 (v/v) Hex:EtOAc→ EtOAc) afforded the title compound as a golden yellow oil.