Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[N:21]1.C(N(CC)CC)C.O>CN(C)C=O>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:3]=3)[CH2:34][CH2:33]2)=[O:31])=[N:21]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: Clc1nc(-c2ccccc2)ns1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a solution of 5-chloro-3-phenyl-1,2,4-thiadiazole (109 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 148 mg (52.3%) of the desired product. mp 234-235° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3[CH:24]=[CH:25][CH:26]=[CH:27][C:18]2=3)=[O:16])=[CH:11][CH:10]=1>O.O1CCOCC1>[N:17]1([C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][C:6]([OH:28])=[O:5])=[CH:14][CH:13]=2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]1=2
Reactant: COC(=O)CCc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Lithium hydroxide monohydrate (114 mg, 2.72 mmol) was added to a solution of 3-[4-(2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-propionic acid methyl ester from Example E65.3 (415 mg, 1.23 mmol) in water (5 ml) and dioxan (20 ml). The mixture was stirred for 18 h at room temperature then concentrated in vacuo. The residue was dissolved in chloroform, washed with 1M HCl solution then brine, dried and concentrated in vacuo to yield the title compound (241 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[C:12]([NH:15]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=[C:10]([CH:35](OCC)[O:36]CC)[N:9]=2)=[C:4]([F:42])[C:3]=1[O:43][CH3:44].S(=O)(=O)(O)O.C(Cl)Cl>C(#N)C.O>[NH2:15][C:12]1[C:13]([F:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:43][CH3:44])[C:4]=2[F:42])[N:9]=[C:10]([CH:35]=[O:36])[CH:11]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: COc1c(Cl)ccc(-c2nc(C=O)cc(N)c2F)c1F

Procedure:
In a typical reaction, 2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine is treated with a 1 M (molar) solution of sulfuric acid in a mixture of acetonitrile-water. The mixture is heated at reflux until the reaction is complete. The mixture is added to methylene chloride, and the organic layer is separated, washed with brine and dried. The solvent is evaporated to provide crude 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinaldehyde.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O.[OH-].[Li+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])([O-:10])=[O:9]
Reactant: N#Cc1ccccc1N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 19 h
Yield: 72.4 %

Procedure:
Combine 1-fluoro-2-nitro-benzene (5.00 g, 35.44 mmol), 2-amino-benzonitrile (4.19 g, 35.44 mmol), lithium hydroxide monohydrate (2.97 g, 70.87 mmol) and DMSO (50.0 ml). Stir the mixture at 55 ° C. for 19 hours then cool to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dry the precipitate under vacuum to give 6.14 g (72%) of an orange solid: mp 134–138°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>>[CH3:12][Si:13]([CH3:15])([CH3:14])[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN([Si](C)(C)C)CC1

Procedure:
In an alternative method, ethyl piperidin-4-ylcarboxylate was reacted with trimethylsilyl chloride, yielding ethyl N-trimethylsilylpiperidin-4-ylcarboxylate (B). Intermediate (B) was then reacted with a two to three molar excess of the Grignard reagent of an appropriately substituted halide, as described above, affording a 4-[bis(substituted)hydroxymethyl]piperidine (C), for example 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. Intermediate (C) was reacted with an appropriately substituted phenylalkyl halide, as described above, yielding the corresponding intermediate N-(substituted alkyl)-4-[bis(substituted)hydroxymethyl]piperidine (I). The N-oxide of (I) and the targeted salts and betaines were prepared as describes above.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]([Cl:26])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:26][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 180 °C
Yield: 57.3 %

Procedure:
A mixture of (5)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 80 mg), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 9, 122 mg) and DIPEA (0.134 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 min) to give the titled compound as solid (90 mg). NMR 10.34 (s, 1H), 8.91 (s, 3H), 8.30 (s, 1H), 5.94 (s, 1H), 4.96-5.34 (m, 1H), 2.25 (s, 3H), 1.56 (d, 3H); m/z 350.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([NH:14][S:22]([C:20]2[CH:21]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=2[CH3:26])(=[O:23])=[O:24])=[N:12][CH:13]=1
Reactant: Nc1ccc(-c2ccccc2Cl)cn1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1ccc(-c2ccccc2Cl)cn1
Yield: 56.9 %

Procedure:
A solution of 0.2 g (0.98 mmol) of 5-(2-chloro-phenyl)-pyridin-2-ylamine and 0.23 g of 5-fluoro-2-methyl-benzenesulfonyl chloride (1.1 mmol) in pyridine (10 ml) was stirred at RT until completion of reaction according to HPLC analysis (48 h). After concentration in vacuo the residue was taken up in EtOAc, the solution washed with 1 N aqueous HCl, saturated brine then dried over sodium sulphate and concentrated in vacuo. The precipitate was collected by filtration and dried in a high vacuum to give 0.21 g (57%) of N-[5-(2-chloro-phenyl)-pyridin-2-yl]-5-fluoro-2-methyl-benzenesulfonamide as an off-white crystalline solid. ISN mass spectrum, m/e: 375.2 (M−1 calculated for C18H14ClFN2O2S: 375).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc(C=O)c2CC1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CN1CCc2c(Cl)ccc(CO)c2CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 46.6 %

Procedure:
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carboxaldehyde (3.07 g, 13.8 mmol) in methanol (35 ml) was cooled to 5° C. and treated with sodium borohydride (3.07 g, 81 mmol). The mixture was stirred for 15 minutes at 5° C. and for 45 minutes at 25° C. The mixture was cooled and carefully treated with dilute hydrochloric acid. The mixture was diluted with brine, basified with 10% sodium hydroxide and extracted with ethyl acetate. The organic phase was dried, concentrated and the residue chromatographed on silica gel eluted with a gradient of methanol-methylene chloride (5:95-9:91) to give 1.45 g (47%) of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-methanol; mp 136.5°-140° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>C1COCC1.[Cu](Br)Br>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:11])[CH2:12][CH2:15][CH:14]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Br
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Agent: Br[Cu]Br
Solvent: C1CCOC1
Product: C=CCC[C@H](O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2S)-2-[(benzyloxy)methyl]oxirane (50 g, 305 mmol) in THF (1500 mL) at 0° C. was added copper bromide (4.37 g, 30.5 mmol). The resulting solution was stirred at 0° C. for 10 minutes and allylmagnesium bromide (1M in THF, 335 mL, 335 mmol) was added. The reaction was stirred for 2 hours at 0° C. and then quenched at 0° C. with saturated aqueous NH4Cl and diluted with DCM. The mixture was stirred at ambient temperature for 20 minutes and filtered to remove insoluble material. The filtrate was extracted with DCM (3×) and the combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography eluted with 10 to 40% EtOAc/hexanes provided (2S)-1-(benzyloxy)hex-5-en-2-ol. 1H NMR (400 MHz, CDCl2): δ 7.37-7.26 (m, 5 H); 5.88-5.74 (m, 1 H); 5.08-4.93 (m, 2 H); 4.54 (s, 2 H); 3.83 (s, 2 H); 3.53-3.44 (m, 1 H); 3.33 (dd, J=9.1, 8.2 Hz, 1 H); 2.49 (s, 1 H); 2.30-2.00 (m, 2 H); 1.64-1.39 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH3:21])[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH3:21])[C:9]2[N:10]=[C:11]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(O)c2cnc(S(C)(=O)=O)nc2n(C)c1=O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cnc(N3CCCC3)nc2n(C)c1=O

Procedure:
A stirred mixture of 3.27 g. (0.01 mole) of 7,8-dihydro-5-hydroxy-8-methyl-2-(methylsulfonyl)-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester and 0.71 g. (0.01 mole) of pyrrolidine in 50 ml. of ethanol was heated under reflux for 1 hour. The mixture was cooled and was filtered. The filter cake was recrystallized twice from ethyl acetate to afford 1.1 g. of title product--m.p. 174°-177° C.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27]C(OCC)C)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:42]C2CCCCO2)[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:33][C@@H:23]([CH2:22][CH2:21][C@H:20]([C@@H:19]1[C@:35]2([CH3:41])[C@H:16]([C@H:15]3[C@H:38]([CH2:37][CH2:36]2)[C@:39]2([CH3:40])[C:12]([CH2:11][C@@H:10]([OH:42])[CH2:9][C@@H:8]2[OH:7])=[CH:13][CH2:14]3)[CH2:17][CH2:18]1)[CH3:34])[C:24]([OH:27])([CH3:25])[CH3:26]
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C[C@H](CC[C@H](F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
A mixture of 0.356 g. (0.00053 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene, 15 ml. of methanol and 0.05 g. of p-toluenesulfonic acid monohydrate was stirred at 25° for 3 hr. The mixture was quenched with 0.25 g. of sodium bicarbonate and stirring for 0.5 hr. The mixture was evaporated to dryness. The residue was triturated with ethyl acetate, filtered, and evaporated to dryness to yield [1α,3β,24S]-24-fluorocholest-5-en-1,3,25-triol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[C:12]([C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[C:8]=1[CH3:9])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: Cc1csc2ccc(F)cc12
Product: CC(=O)c1sc2ccc(F)cc2c1C

Procedure:
The titled compound (7.43 g) was prepared as colorless crystals from 5-fluoro-3-methylbenzo[b]thiophene (9.97 g) and acetyl chloride (5.55 ml) by the similar reaction and purification procedure as described in Reference Example 35.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:17]([NH:18][C:19](=[O:29])[CH:20]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C:21]([OH:23])=[O:22])[C:16](=[O:30])[N:10]2[C:11]=1[P:12]([O-:15])(=[O:14])[O-:13])(=O)C.[Na+:31].[Na+].[Na+].[OH-].[Na+].[Na+].[Cl-].Cl>CCOC(C)=O>[OH:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:17]([NH:18][C:19](=[O:29])[CH:20]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C:21]([OH:23])=[O:22])[C:16](=[O:30])[N:10]2[C:11]=1[P:12]([O-:15])(=[O:13])[O-:14].[Na+:31].[Na+:31].[Na+:31]
Reactant: CC(=O)OCC1=C(P(=O)([O-])[O-])N2C(=O)[C@@H](NC(=O)C(C(=O)O)c3ccsc3)[C@H]2SC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C(C(=O)N[C@@H]1C(=O)N2C(P(=O)([O-])[O-])=C(CO)CS[C@H]12)c1ccsc1
Temperature: 30 °C

Procedure:
Trisodium 3-acetoxymethyl-7β-(2-[3-thienyl]-2-carboxyacetamido)-3-cephem-4-phosphonate (1 g.) is dissolved in 100 ml. of a solution of citrus acetyl esterase (J. D. A. Jeffery, et. al., Biochem. J. (1961) 81, 591). The pH is adjusted to 6.6 and the mixture is maintained at 30° C. 1 N NaOH is added dropwise to maintain the pH at 6.6 as the reaction proceeds and the reaction is continued until no further pH change occurs. 10 g. NaCl is added and the mixture is layered with 50 ml. EtOAc, the pH is adjusted to 2.1 with HCl and the mixture is stirred vigorously. The EtOAc layer is separated and washed once with water and then layered with water and stirred and the pH of the aqueous phase is adjusted to 5.9 with 6 N NaOH. The aqueous layer is separated and freeze-dried to give trisodium 3-hydroxymethyl-7β-(2-[3-thienyl]-2-carboxyacetamido)-3-cephem-4-phosphonate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19][CH3:21])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(COC)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(COC)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a mixture of (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.18 g, 0.64 mmol) and K2CO3 (0.44 g, 3.2 mmol) in acetone was added Me2SO4 (0.16 g, 1.28 mmol). The mixture was stirred at room temperature for 16 hours then diluted with EtOAc. The organic extracts were washed with HCl (aq), dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give (1-hydroxy-6-methoxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.060 g, 32%). 1H NMR (400 MHz, MeOD-d4) δ 7.08 (s, 1H), 6.99 (s, 1H), 5.62 (m, 1H), 5.50 (m, 2H), 4.08 (m, 2H), 3.80 (s, 3H), 3.37 (s, 3H), 3.12 (m, 1H), 2.17 (m, 1H), 1.20 (m, 3H).
Reaction SMILES: O[C:2]([CH:5]1[CH:10]([C:11]([OH:14])([CH3:13])[CH3:12])[CH2:9][CH:8]=[C:7]([CH3:15])[CH2:6]1)([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[CH:10]2[CH:5]([CH2:6][C:7]([CH3:15])=[CH:8][CH2:9]2)[C:2]([CH3:4])([CH3:3])[O:14]1
Reactant: CC1=CCC(C(C)(C)O)C(C(C)(C)O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=CCC2C(C1)C(C)(C)OC2(C)C
Yield: 9.4 %

Procedure:
2-[6-(1-Hydroxy-1-methyl-ethyl)-4-methyl-cyclohex-3-enyl]-propan-2-ol (720 g, 3.3 mol, obtained as detailed above) was loaded into a round bottom flask fitted with a Bidwell-Sterling trap and dissolved in toluene (1 L). An acid catalyst p-toluenesulfonic acid (pTSA, 40 g, 0.18 mol) was added and the mixture was heated to reflux. The reflux was maintained for 1.5 hours. Water was collected in the Bidwell-Sterling trap during this period. GC analysis indicated the completion of the reaction. The resulting mixture was reduced in volume and purified by fractional distillation to provide 1,1,3,3,5-pentamethyl-1,3,3a,4,7,7a-hexahydro-isobenzofuran (60 g, 9% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([Cl:11])[CH:8]=[N:7]1.[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:9]1[CH:8]=[N:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:21]2[CH2:22][CH2:23][N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][CH2:20]2)[CH:10]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Clc1cnn(CCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cnn(CCCCN2CCN(c3ccccc3)CC2)c1

Procedure:
A mixture of 3.56 g (15 mmol) of N-(4-bromo-butyl)-4-chloropyrazole, 2.43 g (15 mmol) of 1-phenyl-piperazine and 2.76 g (20 mmol) of potassium carbonate in 50 ml of dimethylformamide is refluxed for 24 hours. The reaction mixture is evaporated under vacuum, chloroform is added, the mixture is washed with water, dried over sodium sulphate and evaporated under vacuum and 3.1 g of 4-chloro-1-[4-(4-phenyl-1-piperazinyl)-butyl]-1H-pyrazole are obtained, which may be recrystallised from ethyl ether with a melting point of 58°-61° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:16])[C:8]3[N:9]2[CH:12]=[N:13][C:14]=3[CH3:15])=[CH:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:12]1[N:9]2[C:10]3[C:5]([N:6]=[C:7]([CH3:16])[C:8]2=[C:14]([CH3:15])[N:13]=1)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncn2c1c(C)nc1ccc(F)cc12
Product: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Yield: 88.3 %

Procedure:
Reaction of intermediate 4A (1.55 g, 7.2 mmol) and NBS (1.92 g, 10.8 mmol) provided the product 5A as an off-white solid (1.87 g, 89% yield). EIMS 293.9 [M+H]+.
Reaction SMILES: [CH2:1]([Si:5]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[O:6][C:7]1[C:8]([C:13]([O:15]CC)=O)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4].[F:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Cl)=[CH:29][CH:28]=1>O1CCCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:13]([C:8]2[C:7]([O:6][Si:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:15])=[CH:29][CH:28]=1
Reactant: CCCC[Si](CCCC)(CCCC)Oc1cccnc1C(=O)OCC
Reactant: Fc1ccc([Mg]Cl)cc1
Solvent: C1CCOC1
Product: CCCC[Si](CCCC)(CCCC)Oc1cccnc1C(=O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
A solution of ethyl 3-(tributylsilyloxy)picolinate (19 g, 35 mmol) in tetrahydrofuran (100 ml) was cooled to 0° C. and 4-fluorophenylmagnesium chloride (52 ml, 1.0 M in tetrahydrofuran) was added dropwise. After 30 min., the reaction mixture was quenched with water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification on a silica gel column using ethyl acetate-hexane (2:98) as the eluant gave 2-(4-fluorobenzoyl)-3-(tributylsilyloxy)pyridine (3.75 g).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:10](=[O:13])[C:11]=1I.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC.[Sn]>CN(C)C=O.[Pd]>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:10](=[O:13])[C:11]=1[CH:30]=[CH2:31]
Reactant: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(I)c2=O)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: [Sn]
Solvent: CN(C)C=O
Product: C=Cc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)OC)ccc2C)c1=O
Temperature: 60 °C

Procedure:
A round bottom flask containing methyl 3-[4-[(2,4-difluorobenzyl)oxy]-5-iodo-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (2.50 g, 4.88 mmol) in N, N-dimethylformamide was evacuated and flushed with argon. Tributyl(vinyl)tin (2.3 g, 7.3 mmol) and dichlorobis(triphenylphosphine) palladium (II) (0.34 g, 0.49 mmol) were added in the nitrogen atmosphere of a glove box. Heated at 60° C. under argon overnight. Added additional tin (0.7 mL) and palladium (0.17 g) reagents and continued over weekend. No progress observed. Distilled DMF, washed crude product with ethyl acetate, and filtered through celite. The filtrate was concentrated and purified by flash column using 25% ethyl acetate in hexane as eluent. Used without further purification.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH:27]=[O:28])=[CH:20][CH:19]=1>O.CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][CH2:25][CH2:26][CH:27]([OH:28])[CH2:2][C:3](=[O:4])[CH3:5])=[CH:22][CH:23]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=CCCSc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)CC(O)CCSc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 91.4 %

Procedure:
9.86 Grams of methyl acetoacetate were dissolved in 15 ml of water, and 12.67 g of a 30% aqueous sodium hydroxide solution was added thereto by drops while cooling the mixture to 20° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 by adding a concentrated aqueous hydrochloric acid solution thereto. Thereafter, 1.47 g of sodium acetate and then a concentrated aqueous hydrochloric acid solution was added to the mixture so that the mixture had a pH of 6.8. And 50 ml of methanol and then 8.72 g of 3-(4-chlorophenylthio)propanal were added thereto. After having been stirred at 45°-50° C. for 8 hours, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Then the layer was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 13.26 g of crude 6-(4-chlorophenylthio)-4-hydroxy-2-hexanone (purity: 92.3%, yield 91.4%). A purified product was obtained by recrystallization from diisopropyl ether-hexane. The purified product had a melting point of 46.0°-47° C.