Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30].C(Cl)(Cl)Cl>CCOCC.CN(C)C1C=CN=CC=1>[CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][O:21][C:29]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(CO)COCCCCCCCCCCCCCCCC
Reactant: O=C=NCCCCBr
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C=C(COCCCCCCCCCCCCCCCC)COC(=O)NCCCCBr
Temperature: 22 °C
Reaction time: 22 h

Procedure:
3-Hexadecyloxy-2-methylenepropane-1-ol (from Preparation 1) (2.0 g) was dissolved in ether (40 ml). 4-Dimethylaminopyridine (0.16 g) and 4-bromobutyl isocyanate (1.6 g) were added, and the mixture was stirred for 22 hours at 22° C. Chloroform (40 ml) was added, and the mixture was purified through a column of silica gel 60 (70-230 mesh, 20 g) eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on a Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/chloroform 1:1 as eluent.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19]([NH2:20])=[N:18][C:16]2=[O:17])[C@H:12]([OH:23])[C@:11]1([C:25]#[CH:26])[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:33])[CH2:29][C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19]([NH:20][C:30](=[O:31])[CH2:29][N:28]([CH3:33])[CH3:27])=[N:18][C:16]2=[O:17])[C@H:12]([OH:23])[C@:11]1([C:25]#[CH:26])[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CN(C)CC(=O)O
Reactant: C#C[C@@]1(O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc(N)nc2=O)[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C#C[C@@]1(O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc(NC(=O)CN(C)C)nc2=O)[C@@H]1O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Compound 1 (1.9 g, 5 mmol), N,N-dimethylglycine (1.0 g, 10 mmol), N,N-dimethylaminopyridine (0.1 g, 0.8 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.9 g, 10 mmol) were added to DMF (20 mL) under ice-cooling, and the mixture was stirred for one day at 40° C. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL) and saturated brine (50 mL), and then dried over magnesium sulfate. Magnesium sulfate was removed through filtration, and the filtrate was concentrated. The residue was purified through silica gel chromatography (4% methanol/chloroform solvent mixture). The eluate was concentrated, and the residue was recrystallized from hexane, to thereby yield Compound 17 (0.46 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=[CH:14][N:15](C)C)=[C:4]([N+]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H][H]>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:15][CH:14]=[CH:13][C:3]=12
Reactant: COc1ncc(Cl)c(C=CN(C)C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COc1ncc(Cl)c2cc[nH]c12
Yield: 117.5 %

Procedure:
To a solution of Example 108C (12 g, 46.6 mmol) in ethyl acetate (150 mL) was added Raney-Ni (20.0 g, 4.66 mmol), and the reaction mixture was stirred for 20 hours at room temperature under 30 atm. hydrogen. The reaction mixture was filtered and rinsed with ethyl acetate. The filtrate was concentrated to a small volume, and the precipitates were collected by filtration and dried to provide the title compound (10 g, 93% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[CH3:10]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])c1ccccn1
Reactant: CO
Product: COC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
1 g of the complex MoO5 (picolinate]- [H3O]+ was dissolved in 10 ml of methanol and stirred at room temperature for one hour. 0.4 g of a bright yellow solid precipitated from solution at this time and a yield of 29% was obtained. Analysis calculated for MoO9N2C13H12 : C, 35.78%; H, 2.78%; N, 6.42%; O [active], 14.75%; Mo, 22.00%. Found: C, 35.79%; H, 2.90%; N, 6.26%; O [active] 14.11%; Mo, 22.23%. Infrared analysis: [CO]=1745 cm-1 [strong], 1680 cm-1 [strong]; [O--O]=845 cm-1 [strong], 855 cm-1 [strong]; [Mo=O]=945 cm-1 [strong]. Nuclear magnetic resonance [C5ND5 ]: 4.40, singlet, 3H, [C(O)OCH3 ]; 8.2-10.4, multiplet, 8H, [C6H4NCO2 ].
Reaction SMILES: [CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@H:4]([C:15]([O:17]C)=[O:16])[NH:3]1.[OH-].[Na+]>CO>[CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@H:4]([C:15]([OH:17])=[O:16])[NH:3]1
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (1RS,3SR)-trans-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.44 g) is dissolved in methanol (30 ml), and thereto is added 1N NaOH (13 ml). The mixture is stirred at room temperature for 3 hours, and the solvent is distilled off under reduced pressure. The residue is dissolved in water and is acidified with 10% HCl. The precipitated crystals are collected by filtration, washed with water and dried to give the title compound (2.21 g, 90%) as colorless needles, m.p. 242°-244° C. (recrystallized from aqueous ethanol).
Reaction SMILES: OC[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.Cl.C[C:16](C)=[O:17].CCCCCC>CC(C)=O.CCCCCC>[OH:17][CH2:16][C:8]1[C:9](=[O:13])[O:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][CH:12]=2
Reactant: O=c1ccc2ccc(CO)cc2o1
Reactant: CC(C)=O
Agent: Cl
Solvent: CCCCCC
Product: O=c1oc2ccccc2cc1CO
Temperature: 110 °C

Procedure:
In a 25-mm-diameter test tube with a side tubulation for applying vacuum was placed 7-hydroxymethylcoumarin (300 mg, 1.70 mmol) and 2-deoxy-3,5-di-O-p-toluoyl-α-D-ribofuranosyl chloride (600 mg, 1.54 mmol). The test tube was tightly stoppered, and about 1 mm vacuum was applied to the tube through the tubulation. The evacuated tube was then heated in an oil bath at 110° C. for 5 min. During the first 2 min of heating there was vigorous evolution of HCl gas. The reaction mixture was then cooled to room temperature, and the residue was taken up in 3 to 4 ml of a 1:1 mixture of acetone and hexane. The solution was then submitted to chromatography on a 50 mm ×150 mm silica gel column using acetone/hexane 1:1 as the eluant. The fractions containing product were identified by TLC and were pooled and concentrated to a glass. The glass was taken up in 10 ml of ethyl acetate. The ethyl acetate solution in a 50 ml Erlenmeyer flask was placed in a jar containing 20 ml of pentane. The jar was then sealed and the crystallization was allowed to proceed. Yield was 330 mg of white crystals (41% of theory); the melting point was 92°-106° C. Rf =0.48 in acetone/hexane 1:1. NMR showed this material to be approximately a 1:1 mixture of α and β -anomers.
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([O-])=[O:7])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[O:20]1[CH2:3][CH:2]1[CH2:1][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][OH:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOC(C(=O)[O-])c1ccccc1
Solvent: ClCCl
Product: OCC(OCC1CO1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Dissolve 2-(allyloxy)-2-phenylacetate (850 mg, 4.77 mmol) in DCM (40 mL) and add m-chloroperoxybenzoic acid (1.5 g, 8.69 mmol) in a single portion. Stir at ambient temperature overnight. Concentrate under reduced pressure and purify via flash column chromatography using 10% MeOH in DCM to elute. Remove the solvents under reduced pressure to give the product as a colorless oil (900 mg, 97.2%). MS (m/z): 195 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[OH-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>CO.O>[CH3:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:9])[CH:10]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)C=Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
2,4-Dimethylacetophenone (44ak, 1.48 g, 10.0 mmol) and sodium hydroxide (0.54 g, 13.5 mmol) were combined in methanol (30 ml) and stirred for 30 min at room temperature. A solution of benzaldehyde (1b, 1.02 ml, 10.0 mmol) and methanol (30 ml) was added dropwise and the mixture stirred for 18 hr at room temperature. Water (25 ml) was added and the mixture neutralized with hydrochloric acid (1 N). The mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was distilled bulb to bulb to give 1.98 g (84%) of a yellow oil: [expected mp 68° C.]; 1H NMR δ 2.37 (s, 3H), 2.44 (s, 3H), 7.05 (m, 2H), 7.16 (d, 1H, J=16.1 Hz), 7.38 (m, 3H), 7.49 (d, 1H, J=15.9 Hz), 7.54 (m, 3H); 13C NMR: δ 20.4, 21.4, 126.0, 126.6, 128.2, 128.5, 128.8, 130.4, 132.2, 134.7, 136.1, 137.4, 140.8, 145.0, 195.6.
Reaction SMILES: [CH2:1]([N:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]C1C(=O)C(Br)=CC(Br)(Br)C=1>ClCCl>[CH2:1]([N:8]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1)c1ccccc1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Solvent: ClCCl
Product: CCN(Cc1ccccc1)c1ccc(Br)cc1
Reaction time: 20 h
Yield: 76.6 %

Procedure:
N-benzyl-N-phenyl-N-ethylamine (2.25 g, 0.0107 mol) was dissolved in anhydrous dichloromethane (80 mL) and 2,4,4,6-tetrabromocyclohexadiene-1-one (4.36 g, 0.0107 mol) was added in 6 equal portions over a 20 min. period. Stirring was continued at ambient temperature for 20 hours; the organic phase was successively washed with 0.5N solution of sodium hydroxide in water (50 mL), 1N solution of sodium hydroxide in water (50 mL), water (70 mL) and brine (75 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:99) as mobile phase to yield N-benzyl-N-(4-bromophenyl)-N-ethylamine (2.38 g, 0.0082 mol) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][O:19][C:20]([N:22]4[CH2:25][CH2:24][CH2:23]4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:27])=[C:15]([CH2:18][O:19][C:20]([N:22]4[CH2:25][CH2:24][CH2:23]4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(COC(=O)N4CCC4)CS[C@H]23)cs1
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(COC(=O)N2CCC2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 54 %

Procedure:
The compound obtained in Example 8 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 54%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17](=[N:34][N:35]([CH3:37])[CH:36]=3)[N:18]=[C:19]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:19]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16]3[C:17](=[N:34][N:35]([CH3:37])[CH:36]=3)[N:18]=2)=[CH:28][CH:29]=1
Reactant: Cn1cc2c(-c3ccc(OCc4ccccc4)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Agent: [Pd]
Solvent: CCO
Product: Cn1cc2c(-c3ccc(O)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reaction time: 48 h
Yield: 76.9 %

Procedure:
To a solution of 4-(4-benzyloxyphenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (112 mg, 0.2 mmol, obtained in example 252) in EtOH (13 mL), 10% Pd/C (20 mg) was added and it was hydrogenated under atmospheric pressure at room temperature for 2 days. It was filtered through celite, washed with EtOH and concentrated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 61 mg of the title compound (yield: 67%)
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C.C(Cl)Cl>[CH2:9]([N:16]1[C:6](=[O:8])[CH:7]=[C:2]([Br:1])[C:3]1=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1C=C(Br)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of bromomaleic anhydride (1 g, 5.7 mmol) and benzyl amine (0.7 mL, 6.8 mmol) in acetic acid (15 mL) was warmed to 50° C. and stirred overnight. The reaction was then cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with NaHCO3 (3×25 mL) and brine (25 mL). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified using gradient flash chromatography (0-100% ethyl acetate in pet ether) to provide 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (18). 1H NMR (400 MHz, CDCl3) δ 4.71 (s, 2H), 6.87 (s, 2H), 7.26-7.37 (m, 5H). A stirred solution of 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (0.26 g, 1.0 mmol) and p-tolylboronic acid (0.16 g, 1.2 mmol) in dioxane (10 mL) was degassed with a stream of nitrogen for 10 minutes before being treated with CsF (0.39 g, 2.6 mmol) and C12Pd(dppf).CH2Cl2 (0.05 g, 0.06 mmol). The reaction was stirred at room temperature for 1 h then warmed to 40° C. for 1 h. The mixture was then cooled, diluted with CH2Cl2 (30 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified using gradient flash chromatography (0-10% ethyl acetate in pet ether) to provide the title compound 15.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[C:11](=[NH:15])OCC)[CH3:2].[NH2:16][NH:17][C:18]([NH2:20])=[S:19]>>[CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[C:11]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[NH:15])[CH3:2]
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1CC
Reactant: NNC(N)=S
Product: CCn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S

Procedure:
According to the above procedure, ethyl 1-ethyl-5-nitro-2-imidazolecarboximidate and thiosemicarbazide are allowed to react to give 1-(1-ethyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide (IIIN).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH2:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Br[C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH:12][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
Temperature: 100 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine (5.0 g, 18 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (7.0 g, 25 mmol) and N,N-diisopropylethylamine (9.4 mL, 54 mmol) in ethanol (100 mL) was heated at 100° C. (flushed with nitrogen) overnight. The reaction mixture was cooled, poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified on silica gel (eluting with 0-65% ethyl acetate in hexane) to afford the desired product. LCMS calculated for C20H24BrClN5O2 (M+H)+: m/z=480.1, 4821. found: 480.0, 482.1.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.C(Cl)(Cl)Cl>CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Solid NaBH4 (2.55 g, 0.067 mol) was added portion-wise to a solution of p-methoxybenzophenone (25.14 g, 0.118 mol) in MeOH (150 mL) at room temperature over 10 min. After the exothermic reaction had subsided, the reaction mixture was stirred at room temperature for 2 h. TLC (SiO2, CHCl3) indicated incomplete reaction; therefore, additional NaBH4 (2.55 g) was added and the reaction mixture was stirred at room temperature an additional 2 h. The MeOH was evaporated and the residue partitioned between water (100 mL) and CH2Cl2 (100 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (200 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give the alcohol (25.24 g, 99%) as a white solid: m.p. 66-67° C. The structure was confirmed by 1H--NMR in CDCl3.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.CCOC(C)=O>[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1ccccc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(Oc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (0° C.) mixture of phenol (190 mg, 2.02 mmol) and triphenylphosphine (680 mg, 2.6 mmol) in dry THF (6.4 mL) is added dropwise over 30 min a solution of 1-benzyl-piperidin-4-ol (490 mg, 2.6 mmol) and diethylazadicarboxylate (0.41 mL, 2.6 mmol) in dry THF (4.8 mL). The mixture is stirred at room temperature under nitrogen for 20 h. The mixture is dissolved in EtOAc, washed with sat. NaHCO3 (2×20 mL), dried (MgSO4), filtered and concentrated to provide a crude oil. Flash chromatography (EtOAc/Hex: 3/7) provides the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[C:29]([Cl:31])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([CH:19]3[C:27]4[NH:26][N:25]=[CH:24][C:23]=4[CH2:22][CH2:21][CH2:20]3)[C:15]2=[O:28])=[C:11]([Cl:32])[CH:10]=1)C1C=CC=CC=1.CS(O)(=O)=O>CSC>[Cl:31][C:29]1[CH:30]=[C:9]([OH:8])[CH:10]=[C:11]([Cl:32])[C:12]=1[CH2:13][C@@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[C:27]3[NH:26][N:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)[C:15]1=[O:28]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCCc2cn[nH]c21
Agent: CS(=O)(=O)O
Solvent: CSC
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCCc2cn[nH]c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.6 %

Procedure:
To a solution of (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-1H-indazol-7-yl)-pyrrolidin-2-one (2.46 g, 5.23 mmol) in dimethylsulfide (28 mL), add methane sulfonic acid (8.23 g, 85.7 mmol) and stir the mixture vigorously under at room temperature for 18 hours. Remove the solvent in vacuo and dilute the residue with water, adjust the pH to pH=7 with 5 N NaOH, and extract the mixture several times with ethyl acetate and THF. After drying the combined organic layer (Na2SO4), filter and concentrate under vacuum to afford 2.20 g (100%) of the title compound. MS (m/z): 381 (M+).
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[CH2:8]1[CH2:14][S:11](=[O:13])(=[O:12])[O:10][CH2:9]1>O1CCCC1.O>[OH:4][CH2:3][C@@H:2]([NH:1][CH2:9][CH2:8][CH2:14][S:11]([OH:13])(=[O:12])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)[C@H](N)CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of (S)-(−)-2-amino-3-methyl-1-butanol (2.50 g, 24.2 mmol) in tetrahydrofuran (35 mL) was slowly added 1,3-propane sultone (2.89 g, 23.0 mmol). The mixture was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was suspended in 80% acetone/ethanol (75 mL). The suspension was stirred at reflux for 30 seconds. The solid product was collected by filtration, and dried in a vacuum oven (50° C.), to afford compound EP (2.9 g, 56%). 1H NMR (D2O, 500 MHz) δ ppm 3.78 (dd, 1H), 3.62 (dd, 1H), 3.13 (m, 2H), 2.90 (m, 1H), 2.88 (t, 3H), 1.90 (m, 3H), 0.90 (d, 3H), 0.84 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 64.74, 57.24, 48.20, 44.44, 26.98, 21.49, 18.53, 17.00. [α]D=+4.1° (c=0.0017 in water), ES-MS 224 (M−1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]3([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:16]=2)=[CH:10][CH:9]=1)=O.Cl.[NH2:31][OH:32]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[N:31][OH:32])[C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]3([O:28][CH3:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:16]=2)=[CH:10][CH:9]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(=O)c4nccs4)cc3)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(C(=NO)c4nccs4)cc3)c2)CCOCC1
Yield: 40 %

Procedure:
Using an analogous procedure to that described in Example 12, 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl 2-thiazolyl ketone was reacted with hydroxylamine hydrochloride to give in turn the geometric isomers of 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl 2-thiazolyl ketone oxime:Isomer A in 40% yield, m.p. 153°-154° C.,
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH:12]=[O:13])([CH3:6])([CH3:5])[CH3:4]>ClCCl.CO>[C:3]([C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([O:15][CH3:16])=[C:11]([CH2:12][OH:13])[CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1c(C=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1c(CO)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At approx. 10° C., 0.65 g sodium borohydride are added to a solution of 3.75 g 5-tert-butyl-2-methoxy-3-nitro-benzaldehyde in 15 ml dichloromethane and 15 ml of methanol. The solution is stirred for 2 h at ambient temperature and then evaporated down. The residue is combined with aqueous acetic acid and extracted with ethyl acetate. The combined extracts are washed with water and with saturated aqueous saline solution, dried (MgSO4) and evaporated to dryness.