Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Br:24])[CH:17]=1)C1C=CC=CC=1.[CH3:26]CN(C(C)C)C(C)C.CC(C)=O>Cl[Ti](Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:18]1[CH:17]=[C:16]([C@@H:15]2[C:12]([CH3:8])([CH3:26])[O:11][C:10](=[O:13])[NH:9][CH2:14]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc([C@H]2CNC(=O)OC2(C)C)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 141.8 %

Procedure:
To a round bottom flask were added 10 mL DCM and (S)-4-benzyl-3-(2-(3-bromo-4-methoxyphenyl)acetyl)oxazolidin-2-one (1.0 g, 2.47 mmol). TiCl4 (2.6 mL, 2.60 mmol, 1M DCM solution) was added at 0° C. After stirring at 0° C. for 5 mins, DIEA (0.45 mL, 2.6 mmol) was added via syringe. The reaction mixture was stirred at 0° C. for 30 mins. Acetone (0.27 mL, 3.71 mmol) was added followed by more of TiCl4 (2.6 mL, 2.6 mmol, 1 M DCM solution). The reaction mixture was stirred at 0° C. for 2 hrs. It was quenched by addition of 80 mL sat. NH4Cl aqueous solution. The resulting reaction mixture was extracted with 120 mL EtOAc/hexane (1:1). Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on Combiflash prepacked silica gel column, eluted with 5% to 40% EtOAc in hexane to give 1.1 g desired product as viscous material. 1H NMR (500 MHz, CDCl3): δ 7.70 (s, 1H), 7.1-7.4 (m, 6H), 6.88 (d, J=8.5 Hz, 1H), 4.68 (m, 1H), 4.1 (m, 2H), 3.93 (s, 3H), 3.83 (s, 1H), 3.43 (dd, J=3.4, 13.3 Hz, 1H), 2.82 (dd, J=9.9, 13.3 Hz, 1H), 1.46 (s, 3H), 1.09 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:4]([C:5](O)=[O:6])[CH:3]1[C:8]([OH:10])=[O:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH:4]2[C:5]([O:9][C:8](=[O:10])[CH:3]12)=[O:6]
Reactant: CC1(C)C(C(=O)O)C1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)C2C(=O)OC(=O)C21
Reaction time: 3 h

Procedure:
To a solution containing the product (caronic acid) of step 1 (10 g) in toluene (35 mL) was added trifluoroacetic anhydride (17.9 mL) over 10 min. The mixture was heated to reflux while simultaneously distilling out trifluoroacetic acid and excess trifluoroacetic anhydride. When the temperature reached 100-110° C., additional toluene (20 mL) was added and the reaction mixture was heated under reflux. After 3 h, the mixture was concentrated to about 30 mL. Toluene (70 mL) was added and the mixture once again concentrated to about 30 mL. This solution which contained the compound of formula II (assayed by 1H NMR using ρ-nitromethylbenzoate as an internal std) was used in the first step of Example 2 without further purification. Alternatively, the compound formula II can be purified by methods such as fractional distillation.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:27])=[C:6]([C:23]([F:26])=[CH:24][CH:25]=1)[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([OH:18])=O)[C:12](=[O:14])[CH:13]=1)[CH3:2].[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH:40][C:16](=[O:18])[CH:15]([N:11]3[C:12](=[O:14])[CH:13]=[C:8]([O:7][C:6]4[C:23]([F:26])=[CH:24][CH:25]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:27])[CH:9]=[N:10]3)[CH2:19][CH:20]([CH3:21])[CH3:22])=[N:36]2)[CH2:31][O:30]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCOc1ccc(F)c(Oc2cnn(C(CC(C)C)C(=O)O)c(=O)c2)c1F
Product: CCOc1ccc(F)c(Oc2cnn(C(CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c1F

Procedure:
Using the method described in Example 49, 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (Intermediate 92) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as an off-white solid as a mixture of diastereoisomers (164 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>[Pd].CCCCC>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCCCC
Product: CC1(C)CCC(=O)CC1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
4,4-dimethyl-cyclohexen-1-one (5 g, 40.3 mmol) were placed in a hydrogen reaction vessel and n-pentane (15 ml) was added, and Pd/C (500 mg) was added thereto. The hydrogen reaction vessel was pressurized with hydrogen (25 psi), and the reaction was conducted for 30 minutes. After completing the reaction, the solid like material was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound (5 g, 98%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:7](/[CH:19]=[C:20](/[C:27]2[NH:31][N:30]=[N:29][N:28]=2)\[CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[C:8]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[N:9]=1)[CH2:2][CH2:3][CH3:4].Cl>>[CH2:1]([C:5]1[N:6]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:7](/[CH:19]=[C:20](/[C:27]2[NH:31][N:30]=[N:29][N:28]=2)\[CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO[Si](C)(C)C(C)(C)C)c(/C=C(\Cc2cccs2)c2nnn[nH]2)n1Cc1ccccc1Cl
Agent: Cl
Product: CCCCc1nc(CO)c(/C=C(\Cc2cccs2)c2nnn[nH]2)n1Cc1ccccc1Cl

Procedure:
The title compound is prepared by reacting (E)-1-[2-n-butyl-1-{(2-chlorophenyl)methyl}-4-(t-butyldimethylsilyoxy)methyl-1H-imidazol-5-yl)-2-(1H-tetrazol-5-yl]-3-(2-thienyl)-1-propene with dilute hydrochloric acid.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:23])[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:24].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[F:24][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])[N:8]([CH3:23])[C:7]=2[C:2]=1[C:28]1[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=1
Reactant: OB(O)c1ccncc1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(-c3ccncc3)c2n1C
Temperature: 140 °C
Yield: 18.8 %

Procedure:
A mixture of [(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine, (0.10 g, 0.26 mmol), 4-pyridylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 45 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 433 as a white solid (0.019 g, 20%). LCMS (Method K): RT 2.10 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.70 (1H, s), 8.70 (2H, s), 8.25-8.13 (2H, m), 7.95 (1H, d), 7.71 (1H, dd, J=8.80, 4.80 Hz), 7.53 (2H, d, J=17.59 Hz), 7.17 (1H, dd, J=10.45, 8.79 Hz), 5.85-5.73 (1H, m), 3.30 (3H, s), 1.66 (3H, d, J=6.75 Hz). Signals split due to presence of tautomers
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].[CH3:15][NH2:16]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:16][CH3:15])=[O:6]
Reactant: CN
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Product: CNC(=O)c1cc(O)cc(C(F)(F)F)c1

Procedure:
Prepared from 3-hydroxy-5-(trifluoromethyl)benzoic acid and methylamine using the method of preparation 58 to give the title compound as a pale orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]([F:36])([F:35])[CH2:33]I>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]([CH2:33][C:32]([F:36])([F:35])[F:31])[C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)CI
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CC(F)(F)F)c3cc(F)ccc32)CC1
Temperature: 45 °C

Procedure:
Solid 1-tert-butoxycarbonyl-4-(5-fluoro-2-oxo-1-benzimidazolinyl)piperidine (9.7 g, 28.9 mmol.) was dissolved in anhydrous DMF (72 mL) under an inert atmosphere and cesium carbonate (10.6 g, 32.5 mmol.) was added followed by excess 2,2,2-trifluoroethyl iodide (14.3 mL, 145 mmol.). This reaction mixture was gently warmed at 40-50° C. for an extended period (1-2 days), periodically adding additional 2,2,2-trifluoroethyl iodide (4 mL, 4 mmol in four portions) to drive the alkylation to completion. The cooled reaction mixture was diluted with EtOAc and washed with aq. NaHCO3 and water (3×). The organic layer was dried (Na2SO4) and filtered through a pad of charcoal and the solvent then evaporated. The solid residue was triturated with Et2O and collected to give 1-tert-butoxycarbonyl-4-(5-fluoro-3-(2,2,2-tri-fluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine as a nearly pure white solid. This material was crystallized from CH2C2 to remove a slightly less polar impurity affording the product, mp: 172-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:4]=1.O=P(Cl)(Cl)[Cl:23].C(N(CC)C(C)C)(C)C>C(Cl)CCl>[Cl:23][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC2CCOCC2)c2c(=O)[nH]cnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 100 °C

Procedure:
A mixture of 7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4(3H)-one (0.60 g, 2.17 mmol), POCl3 (0.5 mL), and N,N-diisopropylethylamine (1.5 mL) in ClCH2CH2Cl (6 mL) was heated at 100° C. for 4 hours. After the solvent and reagents were evaporated under reduced pressure, toluene was added to the residue, and the solution was evaporated under reduced pressure. The residue was dried under vacuum to afford 4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline as a brown solid. LC-MS (ESI) m/z 295 (M+H)+.
Reaction SMILES: [C:1](=[NH:10])([O:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[CH2:12]CO>>[C:2]1([C:1]2[O:8][CH2:9][CH2:12][N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: COC(=N)c1ccccc1
Product: c1ccc(C2=NCCO2)cc1

Procedure:
The methods (1) to (6) will be described more specifically. For example, as the method (1), potassium hydroxide or acetic anhydride is reacted to 2-chloroethylformamide to provide 2-oxazoline, and the case where 2-bromoethylbenzamide is used provides 2-phenyl-2-oxazoline (see, for example Non-patent Document 1). As the method (2), thionyl chloride is reacted to 2-formamide ethanol to provide 2-oxazoline, and N-(2-hydroxyethyl)benzamide is heated with phosphorous pentoxide to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 2). As the method (3), benzoic acid and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 3). As the method (4), benzonitrile and 2-aminoethanol are heated with calcium chloride at 110 to 120° C. to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 4 and Patent Document 1). As the method (5), methyl benzimidate and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 5). Vinylbenzamide is simply heated to provide 2-phenyl-2-oxazoline. As the method (6), N-allylbenzamide is heated with sulfuric acid to provide 5-methyl-2-phenyl-2-oxazoline (see, for example, Non-patent Document 6).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[C:1]1([C:7]2[CH:8]=[C:9]([C:12]3([CH2:18][NH:19][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=5)[CH:28]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2cc(-c3ccccc3)cs2)CCOCC1
Product: O=C(NCC1(c2cc(-c3ccccc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 20 %

Procedure:
This compound was synthesized from (4-(4-phenylthiophen-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (80 mg, yield 20%). 1H NMR (400 MHz, CDCl3) δ 8.43 (m, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.62-7.58 (m, 3H), 7.45 (d, J=1.2 Hz, 1H), 7.40 (t, J=7.7 Hz, 2H), 7.31 (m, 1H), 7.23 (d, J=1.5 Hz, 1H), 6.15 (t, J=6.5 Hz, 1H), 3.96-3.91 (dt, J=11.9 Hz, 4.2 Hz, 2H), 3.74 (d, J=6.4 Hz, 2H), 3.71-3.66 (m, 2H), 2.18-2.14 (m, 2H), 2.08-2.03 (m, 2H). MS (ESI) m/z: Calculated for C26H22F3N3O3S: 513.13. found: 514.2 (M+H)+.
Reaction SMILES: C[CH2:2][O:3]C(C1N(C(OC(C)(C)C)=O)C2=NC=C(OC(=O)C3C=CC=CC=3)C=C2C=1)=O.[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@H:52]([O:54][CH3:55])[CH3:53])=[C:44](Br)[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@H:52]([O:54][CH3:55])[CH3:53])=[C:44]([CH:2]=[O:3])[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Reactant: CO[C@H](C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Product: CO[C@H](C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 15, intermediate c) from (4R,9aR)-7-bromo-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Br:18])=[C:12]([O:19][CH3:20])[CH:11]=2)=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Br:18])=[C:12]([O:19][CH3:20])[CH:11]=2)=[CH:4][N+:3]=1[O-:29]
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: COc1cc(Cc2c[n+]([O-])c(N)nc2N)cc(OC)c1Br
Reaction time: 0.08 h

Procedure:
3.4 G. of 2,4-diamino-5-(4-bromo-3,5-dimethoxybenzyl)-pyrimidine were suspended in 40 ml. of dioxane and treated with 2.4 g. of 3-chloroperbenzoic acid with stirring. The temperature rose to 38° C. and, after 5 minutes (no more oxidizing agent was detectable), an additional 1.2 g. of 3-chloroperbenzoic acid were added. A clear solution resulted which, after stirring for 15 minutes, became cloudy. After 2 hours, the white precipitate was removed by filtration under vacuum, washed with a small amount of dioxane and recrystallized from ethanol, whereby there was obtained 2,4-diamino-5-(4-bromo-3,5-dimethoxybenzyl)-pyrimidine N1 -oxide of melting point 277°-278° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][P:15]([C:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[CH3:21])([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][P:15]([C:20]([O:22][CH2:23][CH3:24])([O:25][CH2:26][CH3:27])[CH3:21])([O:17][CH2:18][CH3:19])=[O:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)(OCC)P(=O)(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(C)(OCC)P(=O)(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)OCC
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (Dayal, et al., Steroids, 1990, 55(5), 233-237), a reaction mixture of methyl(2R)-2-(tert-butoxycarbonylamino)-3-(1,1-diethoxyethyl(ethoxy)-phosphoryl)propanoate (10a) (4.11 g, 10.0 mmol) and commercial lithium hydroxide monohydrate (LiOH.H2O) (839 mg, 20.0 mmol) in a mixture of water (20 mL) and methanol (MeOH) (5 mL) is stirred at room temperature. The reaction is monitored by TLC and/or LC/MS to completion. Acidic aqueous work-up and purification by silica gel column chromatography furnish the title compound (2R)-2-(tert-butoxycarbonylamino)-3-(1,1-diethoxyethyl(ethoxy)phosphoryl)propanoic acid (10b) which may be used directly in the next step without further isolation and purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[CH3:19][O:18][C:16]([CH2:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])=[O:17]
Reactant: COC(=O)CCl
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
54.3 g of methyl 3-nitro-benzoate and 29.0 g of methyl chioroacetate are dissolved in 100 ml of dimethylformamide and this solution is added dropwise at −10° C. to a solution of 78.5 g of potassium tert.butoxide in 500 ml of dimethylformamide. The mixture is stirred for another 10 minutes at ambient temperature and after this time the solution is poured onto 350 ml of concentrated hydrochloric acid in 2 l of iced water. The solution is stirred for 0.5 hours and the precipitate obtained is suction filtered and washed with water. The product is recrystallised from 150 ml of methanol and dried in vacuo at 40° C. Yield: 48.3 g (51% of theoretical), contains about 20% of methyl 6-methoxycarbonylmethyl-3-nitro-benzoate
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([O:15][CH2:16][C:17]1[S:18][C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=1)(=[O:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([O:15][CH2:16][C:17]1[S:18][C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:22]([O-:6])=[CH:21][C:20]=2[N:29]=1)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OCc1nc2cnc3ccccc3c2s1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1nc2c[n+]([O-])c3ccccc3c2s1

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (34.7 grams (g) of 77% purity, 155 millimoles (mmol)) was added over a period of 15 minutes to a solution of [1,3]thiazolo[4,5-c]quinolin-2-ylmethyl acetate (U.S. Pat. No. 6,110,929, Example 37 Parts A and B, 20.0 g, 77.4 mmol) in chloroform (500 milliliters (mL)), and the reaction was stirred for two hours at room temperature and subsequently washed with aqueous sodium carbonate (500 mL of 10% weight/weight (w/w)). The organic layer was dried over magnesium sulfate and filtered to provide a solution of (5-oxido[1,3]thiazolo[4,5-c]quinolin-2-yl)methyl acetate in chloroform.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])=[CH:18][N:17]=1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added 4-aminotetrahydropyrane (30 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4) and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (42 mg, 48%) as a white solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:42]=[CH:41][C:38](C=O)=[CH:37][CH:36]=1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[OH:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:27][N:24]2[CH2:23][CH2:22][CH:21]([N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:10](=[O:20])[CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [BH4-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Hydroxybenzaldehyde (139 mg, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+ 459.2655, C29H35N2O3 requires 459.2648; LC-MS: (M+H)+ 459.1, tr 2.84 min.