Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:13]([F:14])=[C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]2)[C:11]([O:22][CH:23]([F:25])[F:24])=[C:10]2[C:5]=1[C:6](=[O:32])[C:7]([C:29]([OH:31])=[O:30])=[CH:8][N:9]2[CH:26]1[CH2:28][CH2:27]1.[Cl-].[Mg+2:34].[Cl-]>>[NH2:3][C:4]1[C:13]([F:14])=[C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]2)[C:11]([O:22][CH:23]([F:24])[F:25])=[C:10]2[C:5]=1[C:6](=[O:32])[C:7]([C:29]([O-:31])=[O:30])=[CH:8][N:9]2[CH:26]1[CH2:27][CH2:28]1.[Mg+2:34].[NH2:3][C:4]1[C:13]([F:14])=[C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]2)[C:11]([O:22][CH:23]([F:24])[F:25])=[C:10]2[C:5]=1[C:6](=[O:32])[C:7]([C:29]([O-:31])=[O:30])=[CH:8][N:9]2[CH:26]1[CH2:27][CH2:28]1
Reactant: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC(F)F)CCN1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Product: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)[O-])cn(C4CC4)c3c2OC(F)F)CCN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
23.0 ml (0.0023 mole) of a 0.1N aqueous solution of sodium hydroxide were added to 1.00 g (0.00234 mole) of 5-amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methylpiperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (prepared as described in Example 30), and the resulting insoluble material was removed by filtration. 0.11 g (0.00115 mole) of anhydrous magnesium chloride was added to the filtrate, and the mixture was stirred at room temperature for 90 minutes. At the end of this time, the resulting precipitate was collected by filtration and washed with water, to give 0.91 g of magnesium [5-amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methylpiperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate] as a yellow powder, melting at 291°-293° C. (with decomposition).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[C:13]2[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[N:11][C:10]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31]C(=O)OC(C)(C)C)=[N:9][C:8]=2[CH2:7]1>C(O)(C(F)(F)F)=O>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:10]1[N:11]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:13]2[C:14](=[O:15])[NH:6][CH2:7][C:8]=2[N:9]=1
Reactant: COc1ccc(CN2Cc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)nc3c2C(=O)NC3)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A mixture of crude tert-butyl (1S,2R)-2-(6-(2,4-dimethoxybenzyl)-5-oxo-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-ylamino)cyclohexylcarbamate (235 mg, 0.390 mmol) in TFA (5 mL) was stirred at 60° C. for 2 h and was then purified by reverse phase preparative HPLC. The fractions were collected, concentrated under reduced pressure, diluted in EtOAc, and basified with an aqueous saturated solution of NaHCO3. The organic extract was dried and concentrated under reduced pressure to give the title compound as a white solid (60 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.60 (m, 10H), 2.32 (s, 3H), 3.16 (m, 2H), 3.92 (br s, 1H), 4.14 (s, 2H), 6.88 (d, J=7.07 Hz, 1H), 7.13 (br s, 1H), 7.22 (t, J=7.45 Hz, 1H), 7.34-7.55 (m, 1H), 7.70 (br s, 1H), 8.01 (br s, 1H), 8.58 (br s, 1H). [M+H] calc'd for C19H24N6O, 353. found, 353.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]([O:23]C(=O)C)[C@H:17]2[O:18]C(=O)C)[C@@H:8]([CH2:39][O:40]C(=O)C)[O:7][C@H:6]1[O:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[C:46]=1[C:52](=[O:54])[CH3:53])(=O)C.[S:55]1[CH:59]=[CH:58][C:57]2[CH:60]=[C:61]([CH:64]=O)[CH:62]=[CH:63][C:56]1=2>>[C@H:16]1([O:15][C@@H:9]2[C@@H:8]([CH2:39][OH:40])[O:7][C@@H:6]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[C:46]=3[C:52](=[O:54])[CH2:53][CH2:64][C:61]3[CH:62]=[CH:63][C:56]4[S:55][CH:59]=[CH:58][C:57]=4[CH:60]=3)[C@H:5]([OH:4])[C@H:10]2[OH:11])[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]([OH:23])[C@H:17]1[OH:18]
Reactant: O=Cc1ccc2sccc2c1
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](Oc3cccc(O)c3C(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: O=C(CCc1ccc2sccc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Yield: 51.8 %

Procedure:
2' -[2,3,6-Tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-β-D-glucopyranosyloxy]-6'-hydroxyacetophenone (1541 mg) and benzo[b]thiophene-5-carbaldehyde (389 mg) are treated in the same manner as in Example 1 to give 2'-[4-O-(α-D-glucopyranosyl)-β-D-glucopyranosyloxy]-6'-hydroxy-3-(5-benzo[b]thienyl)propiophenone (645 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.[CH2:13]([O:15][CH:16]([O:19][CH2:20]C)[CH2:17][NH2:18])C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH3:13][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:18][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: CCOC(CN)OCC
Reactant: Cn1c(C=O)nc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(CNCc1nc2ccccc2n1C)OC
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A solution of 1-methyl-2-formylbenzimidazole (1 g) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 equivalent) and NaCNBH3 (0.85 g, 2 equivalents) at 25° C., stirred for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with saturated NaHCO3 and brine, and concentrated. The residue was chromatographed on silica gel, eluting with 8% methanol/dichloromethane to give 1.2 g (64%) of the title compound.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]3([C:17]([S:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[N:18][CH3:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]3[OH:16])[CH:7]=[CH:6][C:5]=12.CC(C)([O-])C.[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>O1CCCC1>[CH2:36]([O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C:10]1([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1)[C:17]([S:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)=[N:18][CH3:19])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(c2ccc3nccn3c2)CCCCC1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN=C(SCc1ccc(OC)cc1)C1(c2ccc3nccn3c2)CCCCC1OCc1ccccc1
Temperature: -60 °C
Reaction time: 2.5 h
Yield: 39 %

Procedure:
1.04 g of 2-(imidazo[1,2-a]pyridin-6-yl)-2-((4-methoxybenzylthio)(methylimino)methyl)cyclohexanol was suspended in 25 ml of tetrahydrofuran. The obtained suspension was cooled to -60° C., followed by the addition of 300 mg of potassium t-butoxide at once. The obtained mixture was stirred at -60° C. for 2.5 hours, followed by the addition of 0.32 ml of benzyl bromide. The temperature of the obtained mixture was gradually raised to 0° C. in about one hour and the resulting mixture was stirred at 0° C. for 2 hours, followed by the addition of water. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1)] to give 500 mg of (yield: 39%). the title compound as a pale-yellow oil
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[NH2:26]>>[CH3:22][C:23]1[CH:24]=[C:25]([NH:26][C:5]2[N:10]=[C:9]([N:11]3[CH:15]=[CH:14][N:13]=[C:12]3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:8]=[CH:7][N:6]=2)[CH:27]=[C:28]([CH3:30])[CH:29]=1
Reactant: CS(=O)(=O)c1nccc(-n2ccnc2-c2ccccc2)n1
Reactant: Cc1cc(C)cc(N)c1
Product: Cc1cc(C)cc(Nc2nccc(-n3ccnc3-c3ccccc3)n2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-(Methylsulfonyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine (1-3, 100 mg, 0.33 mmol) and 3,5-dimethylaniline (0.21 ml, 1.66 mmol) were combined neat and heated to 100° C. After 1 hour the mixture was heated to 130° C. After 1 hour, the reaction was partitioned between a pH 5.2 citrate solution and DCM. The aqueous phase was extracted 2× with DCM and the combined organic extracts were dried over Na2SO4, filtered, concentrated and cooled to room temperature. Purification by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA) was followed by purification by flash column chromatography (2% MeOH/CH2Cl2) gave the title compound as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.27 (d, J=5.5 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.53 (m, 2H), 7.40 (m, 4H), 7.18 (m, 2H), 7.11 (s, 1H), 6.74 (s, 1H), 6.25 (d, J=5.5 Hz, 1H), 2.32 (s, 6H). mp=183° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]1[CH2:18][N:17]2[N:19]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:21]([C:22]([NH2:24])=[O:23])=[C:16]2[NH:15][CH2:14]1.O.NN>CO>[NH2:3][CH2:12][CH:13]1[CH2:18][N:17]2[N:19]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:21]([C:22]([NH2:24])=[O:23])=[C:16]2[NH:15][CH2:14]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CN1C(=O)c3ccccc3C1=O)C2
Agent: NN
Solvent: CO
Solvent: O
Product: NCC1CNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn2C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
To a solution of 6-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.40 mmol) in CH3OH (5 mL) was added hydrazine hydrate (1 mL, 80% of aqueous solution). The mixture was stirred at 70° C. under N2 for 4 hr, concentrated and purified by chromatography column on 5 g of silica gel eluting with DCM/CH3OH to afford 63 mg (43%) of 6-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as colorless oil. MS (ESI) m/e [M+1]+ 363.9.
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:8]=[N:9][O:10][CH:11]=1)([CH2:5]C)[CH2:3]C.C([Mg]Br)C>>[OH:1][C:2]([C:7]1[CH:8]=[N:9][O:10][CH:11]=1)([CH3:5])[CH3:3]
Reactant: CCC(O)(CC)c1cnoc1
Agent: CC[Mg]Br
Product: CC(C)(O)c1cnoc1

Procedure:
The compound 4-(3-hydroxypentan-3-yl)isoxazole is similarly prepared using ethyl magnesium bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[Cl:16])[OH:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[Cl:16])=[O:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1cnccc1Cl
Agent: [Cr+6]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)c1cnccc1Cl
Reaction time: 18 h
Yield: 65 %

Procedure:
(4-Chlorophenyl)-(4-chloro-pyridin-3-yl)-methanol (7.57 g, 29.8 mmol) was dissolved in dry acetone (150 mL) and chromium (VI) oxide (8.94 g, 89.4 mmol) was added. The reaction mixture was stirred for 18 h and then poured into sat aq NaHCO3 solution (500 mL) and extracted with DCM (2×500 mL). The combined organic layers were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 50 g, Strata SI-1, silica gigatube, DCM (600 mL)) to give (4-chlorophenyl)-(4-chloropyridin-3-yl)-methanone (4.88 g, 65.0%) as a yellow oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[C:24]([O:28][C:29](=[O:64])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]([OH:63])/[CH:38]=[CH:39]/[C@H:40]([O:55][Si](C(C)(C)C)(C)C)[C@@H:41]([O:47][Si](C(C)(C)C)(C)C)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])([CH3:27])([CH3:26])[CH3:25]>O>[C:24]([O:28][C:29](=[O:64])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]([OH:63])/[CH:38]=[CH:39]/[C@H:40]([OH:55])[C@@H:41]([OH:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])([CH3:25])([CH3:26])[CH3:27]
Reactant: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](/C=C/[C@@H](O)CCCCCCCC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H](O)[C@@H](O)/C=C/[C@@H](O)CCCCCCCC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 0.42 h

Procedure:
Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 420 μL, 0.416 mmol) was added to a tetrahydrofuran solution (500 μL) of (9S,12S,13S)-(E)-12,13-di-tert-butyldimethylsiloxy-9-hydroxy-10-octadecaenoic acid t-butyl ester (12) (11.6 mg, 0.189 mmol) at room temperature, and the mixture was stirred for 3 hours and 25 minutes. The temperature of the reaction solution was raised to 70° C., and the solution was stirred for 1 hour and 30 minutes. The temperature of the reaction solution was returned to room temperature, water (1 mL) was added, the mixture was extracted with chloroform (5 mL) three times, and the organic layer was washed with saturated brine (5 mL) dried over sodium sulfate, and concentrated. The resulting colorless oily crude product (20 mg) was separated and purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to obtain (9S,12S,13S)-(E)-9,12,13-trihydroxy-10-octadecaenoic acid t-butyl ester (13) as a colorless oily substance (6.5 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: ClCCNCCCl
Reactant: COC(=O)c1cc2c(N)cccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(N3CCNCC3)cccc2[nH]1
Temperature: 110 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
A mixture of the product of Example 3 (9.5 g, 0.051 mol), bis(2-chloroethyl)amine hydrochloride (10.6 g, 0.06 mol), and potassium carbonate (8.3 g, 0.06 mol) in anhydrous dimethylformamide (30 ml) was heated at 110° C. under argon. Further addition of bis(2- chloroethyl)amine hydrochloride (5.5 g. 0.031 mol) and potassium carbonate (4.2 g, 0.031 mol) were made after 7 h and 16 h. After another 6 h,the reaction mixture was poured into dilute potassium carbonate solution (400 ml) and extracted with ether (3×300 ml) and ethyl acetate (2×250 ml). The extracts were combined, dried (MgSO4), and washed with water (2×200 ml). Evaporation of the solvent in vacuo gave a solid which was recrystallised from ether to give the product (5.0 g) as off-white crystals, m.p. 177°-180° C.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:32].[K+]>O1CCCC1.O>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([I:32])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: [I-]
Reactant: Nc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of amino amide from Example 55 (200 mg) in 75% aqueous tetrahydrofuran 1/3 (10 ml) at −5 C. was added sulphuric acid (0.2 ml) followed by sodium nitrite (0.042 g) in water (1 ml). The resulting reaction mixture was stirred for 40 min before potassium iodide (0.136 g) was added. The reaction mixture was heated at 90 C. for 1 hour, cooled to room temperature and diluted with water and extracted with ethyl acetate. The organic layers were separated and dried over magnesium sulphate. The filtered solution was concentrated under reduced pressure and the crude material purified over silica eluting with hexaneslethyl acetate to give the title compound as a white solid (0.23 g).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:29])[N:11]3[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:32]=[C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[S:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[C:45]([O:44][C:42]([N:39]1[CH2:40][CH2:41][N:36]([C:33]2[S:34][CH:35]=[C:31]([C:15]3[C:6]([O:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:25]([O:27][CH3:28])=[O:26])[C@@H:10]([CH3:29])[CH2:9][CH2:8]4)[N:32]=2)[CH2:37][CH2:38]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: COC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cs2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3csc(N4CCN(C(=O)OC(C)(C)C)CC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
A 50-mL round-bottom flask was charged with (S)-methyl 5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.080 g, 0.20 mmol), tert-butyl 4-(4-bromothiazol-2-yl)piperazine-1-carboxylate (0.083 g, 0.24 mmol), sodium carbonate (0.042 g, 0.40 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.081 g, 0.10 mmol), 1,4-dioxane (10 mL) and water (3 mL). The resulting mixture stirred for 4 h at 80° C. The reaction mixture was cooled to room temperature, filtered through a short pad of Celite, and the filtrate was concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 10:1, dichloromethane/methanol) to afford (S)-methyl 6-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.070 g, 64%) as a light yellow solid. MS (ESI, pos. ion) m/z 543 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH3:8][S:9]([O:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1)(=[O:11])=[O:10]
Reactant: OC1CCSCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 300 ml methylene chloride solution of 14.6 g (0.12 mol) of 4-hydroxytetrahydrothiopyran, 11.5 ml (0.15 mol) of methanesulfonyl chloride and 25.8 ml (0.19 mol) of triethylamine were added at 0° C. and stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride (100 ml) and successively washing with water (100 ml) and saturated saline (100 ml), followed by drying over anhydrous sodium sulfate. The solvent was then distilled off under vacuum to obtain 24.5 g (quant.) of the above-identified compound as a slightly brown crystal.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:47])[C@H:7]([CH3:46])[CH2:8][C@H:9]([OH:45])[C@@H:10]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:11][C@@H:12]([CH:34]([CH3:36])[CH3:35])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[C:16]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6](=[O:47])[C@H:7]([CH3:46])[CH2:8][C@H:9]([OH:45])[C@@H:10]([NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:11][C@@H:12]([CH:34]([CH3:35])[CH3:36])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OCc2ccccc2)c(OCCCOC)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(O)c(OCCCOC)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
1.34 g of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-benzyloxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid (N-butyl)-amide are hydrogenated in the presence of 400 mg of 5% Pd/C in 50 ml of methanol for 10 minutes at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by means of FC (50 g of silica gel, hexane/ethyl acetate=1:1). The title compound is obtained: Rf (hexane/ethyl acetate=1:1)=0.16; HPLC Rt =17.42 minutes; FAB-MS: (M+H)+ =567.
Reaction SMILES: [OH:1]C1C2C(=O)C3C(=CC(O)=CC=3)OC=2C(O)=CC=1.OC1C2C(=O)C3C(=C(O)C=CC=3)OC=2C=C(O)C=1.[OH:37][C:38]1[C:51]2[C:50](=[O:52])[C:49]3[C:44](=[CH:45][C:46]([OH:53])=[CH:47][CH:48]=3)[O:43][C:42]=2[CH:41]=[C:40]([OH:54])[CH:39]=1.OC1C2C(=O)C3C(=CC=CC=3O)OC=2C=C(O)C=1.OC1C2C(=O)C3C(=CC=CC=3)OC=2C=C(O)C=1.OC1C2C(=O)C3C(=CC(O)=CC=3)OC=2C=CC=1>>[OH:37][C:38]1[C:51]2[C:50](=[O:52])[C:49]3[C:44](=[CH:45][C:46]([OH:53])=[CH:47][C:48]=3[OH:1])[O:43][C:42]=2[CH:41]=[C:40]([OH:54])[CH:39]=1
Reactant: O=c1c2ccc(O)cc2oc2cc(O)cc(O)c12
Reactant: O=c1c2ccc(O)cc2oc2c(O)ccc(O)c12
Agent: O=c1c2c(O)cccc2oc2cc(O)cc(O)c12
Agent: O=c1c2ccc(O)cc2oc2cccc(O)c12
Agent: O=c1c2cccc(O)c2oc2cc(O)cc(O)c12
Product: O=c1c2c(O)cc(O)cc2oc2cc(O)cc(O)c12

Procedure:
1,4,6-trihydroxyxanthone; 1,3,5-trihydroxyxanthone; 1,3,6-trihydroxyxanthone; 1,3,8-trihydroxyxanthone; 1,3-dihydroxyxanthone; and 1,6-dihydroxyxanthone.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>O1CCCC1>[CH2:26]([O:25][P:24]([CH2:23][O:4][C:1](=[S:3])[CH3:2])([O:28][CH2:29][CH3:30])=[O:31])[CH3:27]
Reactant: CC([O-])=S
Reactant: CCOP(=O)(CCl)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(COC(C)=S)OCC
Yield: 70.4 %

Procedure:
A solution of tetra-n-butylammonium thioacetate (12.8 g, 0.041 mol) and diethyl chloromethylphosphonate (5 g, 0.027 mol) is stirred in tetrahydrofuran (30 ml) overnight at room temperature. After evaporation of the solvent, the residue is purified by silica gel chromatography (2:1 heptane:acetone as eluant) to give diethoxyphosphinylmethylthioacetate (4.3 g). 1H-NMR: 4H, m, 4.20-4.11 ppm; 2H, d, 3.23; 3H, s, 2.40; 6H, m, 1.33.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:12])[C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([C@:21]2([CH2:32][F:33])[CH2:26][C@@H:25]([C:27]([F:30])([F:29])[F:28])[O:24][C:23]([NH2:31])=[N:22]2)[C:17]([F:20])=[N:18][CH:19]=1>>[NH2:31][C:23]1[O:24][C@H:25]([C:27]([F:28])([F:30])[F:29])[CH2:26][C@:21]([C:16]2[CH:15]=[C:14]([NH:13][C:9](=[O:11])[C:6]3[C:5]([CH3:12])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:19]=[N:18][C:17]=2[F:20])([CH2:32][F:33])[N:22]=1
Reactant: NC1=N[C@](CF)(c2cc(N)cnc2F)C[C@@H](C(F)(F)F)O1
Reactant: Cc1cc(C#N)cnc1C(=O)O
Product: Cc1cc(C#N)cnc1C(=O)Nc1cnc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1

Procedure:
The title compound was synthesized using procedures analogous to those described in Method H Step 2 (Example 66) above, but using 5-cyano-3-methylpicolinic acid and (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (12k, as described in Example 138, method S). MS m/z=455.1 [M+H]+. Calculated for C19H15F5N6O2: 454.4