Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.Cl>C(O)C.[OH-].[Na+]>[F:33][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2nc3cc(-c4c(F)cncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2nc3cc(-c4c(F)cncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 60 °C
Yield: 84.7 %

Procedure:
To a solution of methyl 4-[6-(3,5-difluoropyridin-4-yl)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridin-2-yl]benzoate (0.05 g, 0.11 mmol) in ethanol (1.1 mL), 2N sodium hydroxide aqueous solution (0.11 mL) was added. The mixture was heated at 60° C. for 5.5 h and then neutralised with 2N hydrogen chloride aqueous solution. The solvent was evaporated and the crude mixture was suspended in water, the solid formed was filtered and dried to give the title compound (0.04 g, 76% of yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:15]O>>[CH3:15][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(OC)c(Br)c1

Procedure:
To 3-bromo-4-methoxyphenylacetic acid (1.0 g, 4.1 mmol) in MeOH (20 mL) was added HCl (4N in 1,4-dioxane; 5 mL, 20 mmol), and the reaction was refluxed overnight. The mixture was concentrated to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2Cl)=[CH:7][C:6]=1[O:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH2:51])=[CH:48][CH:47]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:51][CH2:50][C:49]2[CH:52]=[CH:53][C:46]([F:45])=[CH:47][CH:48]=2)=[CH:7][C:6]=1[O:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(NC(=O)c3cccnc3Cl)ccc2C(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(NC(=O)c3cccnc3NCc3ccc(F)cc3)ccc2C(C)(C)C)CC1
Temperature: 125 °C

Procedure:
N-[4-tert-Butyl-3-(1-Boc-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamide (200 mg), DIEA (145 μL), IpOH (3 mL) and 4-fluorobenzylamine (184 μL) were combined in a sealed tube and heated to 125° C. for 2 days. The mixture was purified by flash chromatography (EtOAc) to provide the product. M+Na 619; Calc'd for C34H43FN4O4: 590.33.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:11][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Cc1ccccc1
Reactant: Nc1cnccc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccncc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Aminoisonicotinic acid (400 mg) was suspended in methanol (6 mL) and toluene (18 mL) was added. A solution of (trimethylsilyl)diazomethane (2.0 M in diethyl ether, 1.88 mL) was added slowly to the suspension. Within 5 to 10 minutes after addition, the suspension turned into a solution. After 2 hours stirring at room temperature, the reaction mixture was quenched with water and extracted 3× with ethyl acetate. The combined organic layer was washed with 2N hydrochloric acid, saturated bicarbonate solution and brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica gel 60, hexane/ethyl acetate=1:2, Rf=0.40) to afford 340 mg of the title compound of the formula
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([NH:37][CH2:38][CH3:39])=[O:36])C1C=CC=CC=1>CO.[Pd]>[CH2:38]([NH:37][C:35]([C:10]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:12]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[C:13]([OH:14])[C:9]=1[OH:8])=[O:36])[CH3:39]
Reactant: CCNC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCNC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Yield: 86.4 %

Procedure:
A solution of 3,4-bis(benzyloxy)-N2-ethyl-1-(4-methoxyphenyl)-N5,N5-dimethyl-1H-pyrrole-2,5-dicarboxamide (UL1-055) (118 mg, 0.22 mmol) in methanol (4.5 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 30° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford N2-ethyl-3,4-dihydroxy-1-(4-methoxyphenyl)-N5,N5-dimethyl-1H-pyrrole-2,5-dicarboxamide (UL1-024) (66 mg, 82%) as a brown solid: m/z 348 (M+H)+ (ES+); 346 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 1H), 8.42 (s, 1H), 7.10-7.03 (m, 1H), 7.02-6.97 (m, 2H), 6.86-6.77 (m, 2H), 3.75 (s, 3H), 3.14-3.06 (m, 2H), 2.81 (br s, 6H), 0.97 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH:3]([O:8][CH2:9][CH2:10][CH3:11])[O:4][CH2:5][CH2:6][CH3:7].CC(O)(CC)C.[OH-].[K+]>COC(C)(C)C>[CH2:5]([O:4][C:3]([O:8][CH2:9][CH2:10][CH3:11])=[CH2:2])[CH2:6][CH3:7]
Reactant: CCCOC(CCl)OCCC
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)(C)O
Solvent: COC(C)(C)C
Product: C=C(OCCC)OCCC
Reaction time: 6 h

Procedure:
270.8 g (1.5 mol) of 1-chloro-2,2-dipropoxyethane, 450 ml of tert.-butyl methyl ether, 19.8 g (0.22 mol) of 2-methyl-2-butanol, 12 g of polyethylene glycol-1000 dimethyl ether and 300 g (4.5 mol) of technical grade potassium hydroxide (91%) were heated under reflux while stirring for six hours. The reaction was stopped, the salts filtered off and the product distilled. The conversion was 86.3% of theoretical. The main fraction contained 148.1 g (68.6% of theoretical) of pure 1,1-dipropoxyethene (b.p. 70° C. at 1.2 kPa) .
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOCCCCl
Reactant: O=C1CCNCC1
Product: CCCCOCCCN1CCC(=O)CC1

Procedure:
1-(3-Butoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-butoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[C:8]1([NH:7][C:5]([C:4]2[CH:3]=[C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=[CH:15][CH:14]=2)=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Nc1ccccc1)c1cccc(O)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1cccc(C(=O)Nc2ccccc2)c1)c1ccccc1

Procedure:
The title product was prepared from 3-hydroxy-N-phenyl-benzamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (54%, white solid). HPLC-MS: m/z=347.2 (M+1); Rt: 4.01 min.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].Br[CH2:9][CH2:10][O:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: BrCCOCCBr
Reactant: COC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1(C#N)CCOCC1
Yield: 61.2 %

Procedure:
Methyl cyanoacetate (2.50 mL, 28.3 mmol) and 2-bromoethyl ether (4.63 mL, 36.8 mol) were dissolved in acetone (50 ml). To this, potassium carbonate (9.78 g, 70.8 mmol) was added and the mixture was heated to reflux for 8 hours. The reaction mixture was filtered and the mother liquid was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (2.93 g, yield: 61%).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[CH:10]\[CH2:11][CH3:12])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:41]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[Cl:19][C:15]1[CH:14]=[C:13]([C:9](=[O:8])[C@H:10]([OH:41])[CH2:11][CH3:12])[CH:18]=[CH:17][CH:16]=1
Reactant: CC/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CC[C@@H](O)C(=O)c1cccc(Cl)c1
Yield: 85.2 %

Procedure:
Compound 10j was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-chlorophenyl)but-1-enyloxy)dimethylsilane (9j, 3.7 g, 0.013 mol), AD-mix-β (17.5 g), and CH3SO2NH2 (1.2 g, 0.0126 mol) in tert-butyl alcohol-water (45 mL:45 mL). The reaction was quenched with sodium sulfite (12.5 g). After purification by column chromatography on silica gel, 2.2 g (79%) of the title product was isolated: [α]20D +31.4° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.91-7.88 (m, 1H), 7.81-7.75 (m, 1H), 7.62-7.56 (m, 1H), 7.45 (t, 1H, J=7.8 Hz), 5.06-4.98 (m, 1H), 3.60 (d, 1H, J=6.5 Hz), 2.04-1.87 (m, 1H), 1.70-1.51 (m, 1H), 0.94 (t, 3H, J=7.4 Hz); 13C NMR (CDCl3) δ 201.4, 135.8, 135.7, 134.2, 130.6, 128.9, 126.9, 74.5, 29.1, 9.2. C10H11ClO2.
Reaction SMILES: I[Si](C)(C)C.[F:6][C:7]1[CH:8]=[C:9]([C@@H:15]2[CH2:24][CH2:23][CH2:22][C@H:21]3[N:16]2[C:17](=[O:25])[CH2:18][CH2:19][CH2:20]3)[CH:10]=[C:11]([F:14])[C:12]=1[F:13].CN(C)CCN(C)C.[I:34]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:14][C:11]1[CH:10]=[C:9]([C@@H:15]2[CH2:24][CH2:23][CH2:22][C@H:21]3[N:16]2[C:17](=[O:25])[CH:18]([I:34])[CH2:19][CH2:20]3)[CH:8]=[C:7]([F:6])[C:12]=1[F:13]
Reactant: O=C1CCC[C@H]2CCC[C@@H](c3cc(F)c(F)c(F)c3)N12
Reactant: II
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1C(I)CC[C@H]2CCC[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Iodotrimethylsilane (1.41 mL) was added to a solution of (6S,9aR)-6-(3,4,5-trifluorophenyl)octahydroquinolizin-4-one (1.79 g) and N,N,N′,N′tetramethylethylenediamine (3.34 mL) in methylene chloride (50 mL) in a nitrogen atmosphere at 0° C., and the reaction solution was stirred at 0° C. for 30 minutes. Iodine (2.41 g) was added to the reaction solution at 0° C., and the reaction solution was stirred at 0° C. for one hour. Ethyl acetate and a saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain (6S,9aR)-6-(3,4,5-trifluorophenyl)-3-iodooctahydroquinolizin-4-one. A mixture of (6S,9aR)-6-(3,4,5-trifluorophenyl)-3-iodooctahydroquinolizin-4-one with triethyl phosphite (20 mL) was stirred at 120° C. for three hours. The reaction solution was left to cool to room temperature, and then the reaction solution was concentrated under reduced pressure. Lithium hydroxide monohydrate (792 mg) was added to a mixed solution of the residue and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (1.64 g) in tetrahydrofuran (45 mL) and ethanol (15 mL) at room temperature, and the reaction solution was stirred at room temperature for four hours. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) and then by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 2.46 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O[CH2:13][CH:14]([CH2:16]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]2[C:8]=1[CH:13]=[CH:14][CH:16]=[N:7]2
Reactant: OCC(O)CO
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c2cccnc12
Yield: 40.7 %

Procedure:
In a similar fashion using route 10 general procedure 20, 5-fluoro-2-nitroaniline (1.0 g, 6.4 mmol), glycerol (1.83 g, 19.86 mmol), 3-nitrobenzenesulfonic acid sodium salt (1.8 g, 8.33 mmol) and H2SO4/H2O (1.2 ml, 7:5) gave the title compound (500 mg, 60%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:8][N:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6]1)=[O:4].Cl.[CH3:16][NH:17][O:18][CH3:19].C([Mg]Cl)(C)C>C1COCC1>[CH3:19][O:18][N:17]([CH3:16])[C:3]([CH:5]1[CH2:6][N:7]([C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH2:8]1)=[O:4]
Reactant: COC(=O)C1CN(c2ncccn2)C1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CN(c2ncccn2)C1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 244.2 %

Procedure:
To a suspension of the above ester (137.3 mg, 0.711 mmol) and N-methyl-O-methyl hydroxylamine hydrochloride (127.6 mg, 1.103 mmol) in THF (5 ml), was added iso-propyl magnesium chloride (2.0 M in THF, 1.067 ml, 2.133 mmol) at −20° C. during 15 minutes. The mixture was stirred at −10° C. for another 30 minutes before it was quenched with the addition of saturated ammonium chloride (10 ml). The mixture was extracted with EtOAc (2×15 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (4% MeOH/CH2Cl2) to give 1-pyrimidin-2-yl-azetidine-3-carboxylic acid methoxy-methyl-amide (385.9 mg, 98%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.32 (d, J=6.4 Hz, 2H), 6.55 (t, J=6.4 Hz, 1H), 4.34 (m, 4H), 3.88 (m, 1H), 3.70 (s, 3H), 3.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](=[O:22])[CH:13](Br)[C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:22])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)C(Br)C(=O)OCC
Reactant: Nc1cccnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1nc2c(N)cccn2c1C(=O)OCC
Yield: 32.8 %

Procedure:
A solution of 2,3-diaminopyridine (13.1 g, 0.12 mol) , 2-bromo-3-oxo-succinic acid diethyl ester (31 g, 0.12 mol) and sodium carbonate (13.2 g, 0.12 mol) in 1,2-dimethoxyethane (200 ml) was refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was suspended in methylene chloride and filtrated through silica gel. The filtrate was evaporated under reduced pressure to give 10.9 g (33%) of the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]1=[O:20].[OH-].[Na+]>>[O:20]=[C:12]1[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13]1
Reactant: COC(=O)CCCCCCCn1c(=O)oc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)oc2ccccc21

Procedure:
The product is produced as described in example 22 from 14.5 g. of 8-(2-oxo-benzoxazolin-3-yl)-caprylic acid methyl ester and 2.4 g. of NaOH. Eluant in chromatographic purification: chloroform.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[Cl:12])[C:5](OC)=[O:6].C(ON=O)(C)(C)C.NC1C(Br)=CC(C(OC)=O)=CC=1Br.N>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[Cl:12])[CH:5]=[O:6]
Reactant: COC(=O)c1cc(Br)c(Cl)c(Br)c1
Agent: CC(C)(C)ON=O
Agent: COC(=O)c1cc(Br)c(N)c(Br)c1
Agent: N
Solvent: CC#N
Product: O=Cc1cc(Br)c(Cl)c(Br)c1
Reaction time: 0.17 h

Procedure:
Methyl 3,5-dibromo-4-chlorobenzoate: CuCl2 (2.82 g, 21.0 mmol) in MeCN (30 mL) was stirred at 80° C. for 30 min. To this mixture tert-butylnitrite (2.7 mL, 23 mmol) was then added dropwise at same temperature and the mixture was stirred for another 10 min. Methyl 4-amino-3,5-dibromobenzoate (5.0 g, 16 mmol) in MeCN (30 mL) was added dropwise to the reaction mixture and then stirred at 80° C. for 30 min. The reaction mixture was brought to ambient temperature and an aqueous ammonia solution (20 mL) was added to the reaction mixture and extracted with petroleum ether. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (4.5 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 2H), 3.94 (s, 3H); ESIMS m/z 326 ([M]+); IR (thin film) 1732, 746 cm−1.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14]O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.O=P(Cl)(Cl)[Cl:24].O>N1C=CC=CC=1>[Cl:24][CH2:14][CH2:13][C:12]#[C:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[N:5]=[CH:4]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Solvent: O
Solvent: c1ccncc1
Product: Fc1c(C#CCCCl)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a mixture of 4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (4.6 g, 16.0 mmol) in pyridine (50 mL), was added POCl3 (10.3 g, 67.3 mmol). The resulting solution was stirred at room temperature for 2 hours. Upon completion, the reaction solution was poured into water (250 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column (0˜10% EtOAc in petroleum ether) affording the title compound (2.62 g). 1H NMR (300 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 5.87 (dd, 1H), 3.90-3.69 (m, 2H), 3.83 (t, 2H), 2.98 (t, 1H), 2.41-2.29 (m, 1H), 2.06-1.94 (m, 2H), 1.78-1.70 (m, 1H), 1.60-1.54 (m, 2H); LCMS: 307 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:6]=1)(=O)=O.[C-:30]#[N:31].[Na+]>C(#N)C.CS(C)=O>[N:14]1([CH2:13][CH2:12][O:11][C:9]2[CH:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:6]=[C:5]([C:30]#[N:31])[N:10]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(OCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Solvent: CC#N
Solvent: CS(C)=O
Product: N#Cc1nc(OCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
A mixture of 2-methanesulfonyl-4-(2-piperidin-1-yl-ethoxy)-6-(3-trifluoromethyl phenyl)-pyrimidine (50 mg, 0.12 mmol) and sodium cyanide (12 mg, 0.23 mmol) in acetonitrile (1.5 ml) with a few drops of DMSO was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The residue was chromatographed over silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 95/5) to yield 31 mg of the above titled compound, yield: 70%. HPLC: 99.5%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])([O-:8])=[O:7].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[N+:6]([C:9]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:10]=1[C:11]([O:13][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)=[O:12])([O-:8])=[O:7]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(OC1CCCO1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Dihydrofuran (0.03 mole), 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (0.025 mole), methylene chloride (25 ml) and p-toluenesulfonic acid (1 spatula tip) are charged into a glass reaction vessel equipped with a magnetic stirrer. The reaction mixture is stirred at room temperature until the carboxylic acid group can no longer be detected by IR in the mixture. After this time, the reaction mixture is washed with dilute aqueous sodium carbonate and with water. The washed solution was dried and stripped of solvent and unreacted starting material to yield the desired product 2-tetrahydrofuryl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: O[C:2]([CH3:30])([CH3:29])[CH2:3][C@@:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=C[CH:33]=1.COC(OC)(OC)C>C(OCC)(=O)C>[CH3:29][C:2](=[CH2:30])[CH2:3][C@:4]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]3[O:18][C:32]([CH3:33])=[N:20][N:19]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(C(=O)NN)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(C)(OC)OC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)C[C@@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3nnc(C)o3)cc2)C(=O)O1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-benzoic acid hydrazide (90 mg), toluene-4-sulfonic acid monohydrate (10 mg), and 1,1,1-trimethoxy-ethane (1 ml) was stirred at room temperature for 1 h, at 80° C. for 2 h, and finally at reflux temperature for 1.5 h. After cooling to ambient temperature, ethyl acetate was added and the resulting mixture was washed with aqueous NaHCO3 solution and brine. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 99:1->95:5) to afford the title compound in a mixture with the double bond isomer (S)-6-(2-methyl-allyl)-3-{(S)-1-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one (ca. 64:36) as a colorless resin-like solid.