Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.F>C(O)C.[Pt]=O>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Agent: O=[Pt]
Agent: F
Agent: FB(F)F
Solvent: CCO
Product: c1ccc(C2CNc3ccccc32)cc1
Reaction time: 4 h

Procedure:
8.0 G of 3-phenylindole was dissolved in 120 ml of 96% ethanol and 60 ml of 48% hydrofluoroboric acid was added thereto. 0.4 G of platinum oxide was added to the mixture which was hydrogenated at 30 p.s.i. at room temperature for four hours. The catalyst was removed by filtration, the filtrate concentrated to 1/3 of the volume, basified with 50% aqueous sodium hydroxide and then extracted with ether. 6.7 G of a dark oil which was obtained from the ether extracts after removal of the solvent was chromatographed on silica gel to give 4.1 g of 3-phenylindoline as a pale yellow viscous oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:13]C(=O)C)([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[OH-].[K+].Cl.C(OCC)C>C(O)CO.C(#N)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC(C)(C)NC(C)=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Solvent: CC#N
Product: CCc1ccc(CC(C)(C)N)cc1
Temperature: 0 °C

Procedure:
16.3 g (74 mmol) of N-[2-(4-ethylphenyl)-1,1-dimethylethyl]acetamide and 8.0 g of potassium hydroxide are refluxed for 15 hours in 60 mL ethylene glycol. The reaction mixture is combined with ice water and extracted three times with diethyl ether. The combined organic phases are washed with water, dried with sodium sulfate, and freed from solvent. To prepare the hydrochloride, the crude product is dissolved in acetonitrile and ethereal hydrochloric acid and diethyl ether are added successively. The solid precipitated is suction filtered and dried. Yield: 11.0 g (69%, hydrochloride); melting point 165° C.-167° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:9][C:5]1([CH3:8])[N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:3]([CH2:2][O:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:7][O:6]1
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reaction time: 17 h
Yield: 84.7 %

Procedure:
A solution of 10.7 g of t-butyl (R)-4-hydroxymethyl-2,2-dimethyl-3-oxazolid inecarboxylate (J. Org. Chem. 52, 1987, 2361-64) in 107 ml of pyridine is treated with 9.7 g of p-toluenesulphonyl chloride. The reaction mixture is stirred for 17 hours, then taken up in ethyl acetate and washed with water. After drying and evaporation the residue is purified over silica gel with hexane/ethyl acetate (3:1). There are obtained 15.1 g of t-butyl (S)-2,2-dimethyl-4-(p-tolylsulfonyloxymethyl)-3-oxazolidinecarboxylate.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][Si](C)(C)C)[CH2:13][C@H:12]1[CH2:21][O:22][CH3:23])=O)C1C=CC=CC=1.[H][H]>CO>[CH3:23][O:22][CH2:21][C@H:12]1[NH:11][CH2:15][C@H:14]([OH:16])[CH2:13]1
Reactant: [H][H]
Reactant: COC[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)OCc1ccccc1
Solvent: CO
Product: COC[C@@H]1C[C@@H](O)CN1
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To (2S,4R)-2-Methoxymethyl-4-trimethylsilanyloxy-pyrrolidine-1-carboxylic acid benzyl ester 1.00 g (3.98 mmol) in 3 mL of methanol was added 10% Pd(C) 0.10 g and the mixture was stirred under 1 atmosphere of hydrogen for 24 h. The mixture was filtered through a 0.22 μM Teflon filter, concentrated and subsequently put on a high vacuum for 2 h to afford 0.43 g (86%) of (3R,5S)-5-Methoxymethyl-pyrrolidin-3-ol as clear oil. 1H NMR (CDCl3, 400 MHz) δ: 5.30 (1H, s), 4.67 (1H, t, J=5.6 Hz), 4.56 (1H, t, J=7.6 Hz), 4.26-4.21 (1H, m), 4.19 (1H, dd, J=8.1, 3.3 Hz), 3.14 (1H, d, J=12.3 Hz), 2.08 (1H, dd, J=8.2, 3.2 Hz), 1.66-1.59 (3H, m). LCMS (ACPI) (M+H+) m/z: 132.2.
Reaction SMILES: [C:1]1([CH:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15](OC)=[CH:14][CH:13]=2)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(CN)=CC=1>>[C:1]1([CH:7]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(NCc1ccc(OC)cc1)c1ccccc1
Agent: COc1ccc(CN)cc1
Product: C=CC(NCc1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 80 %

Procedure:
N-(1-Phenyl-2-propenyl)-4-methoxybenzylamine (Yadav, J. S.; Bandyopadhyay, A.; Reddy, B. V. S. Tetrahedron Lett. 2001, 42, 6385: The general procedure was followed with 4-methoxybenzylamine (186 mg, 1.35 mmol) and cinnamyl methylcarbonate (199 mg, 1.04 mmol). The reaction was conducted at room temperature for 18 h. 1H NMR analysis of the crude mixture indicated the ratio of regioisomers and diallylation product to be 98/0/2. The mixture was purified by flash column chromatography on silica gel (5% ethyl acetate in hexane) to give the title compound (210 mg, 80%). HPLC analysis indicated that the enantiomeric excess of product was 94% [Daicel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.5 mL/min; detection wave length=230 nm; TR=26.2 (major), 29.3 (minor) min]: [α]DRT=−1.8 (c 5.5, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.21-7.38 (m, 7H), 6.86 (d, J=8.4 Hz, 2H), 5.94 (ddd, J=17.2, 10.0, 7.6 Hz, 1H), 5.22 (dt, J=17.2, 1.4 Hz, 1H), 5.11 (ddd, J=10.0, 1.6, 1.2 Hz, 1H), 4.21 (d, J=7.6 Hz, 1H), 3.80 (s, 3H), 3.68 (d of AB pattern, J=13.0 Hz, 1H), 3.64 (d of AB pattern, J=13.0 Hz, 1H), 1.58 (brs, 1H). 13C NMR (125.77 MHz, CDCl3) δ 158.54, 142.84, 141.01, 132.56, 129.29, 128.49, 127.30, 127.14, 115.05, 113.72, 64.99, 55.24, 50.65.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:19]=1[CH:20]=[O:21].O.O.P([O-])(O)(O)=[O:36].[Na+].Cl([O-])=O.[Na+].ClCCl>CC(=CC)C.C(O)(C)(C)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:19]=1[C:20]([OH:36])=[O:21]
Reactant: O=P([O-])(O)O
Reactant: O=Cc1c(OCc2cccc(OCc3ccc4ccccc4n3)c2)cccc1C(F)(F)F
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: O=C(O)c1c(OCc2cccc(OCc3ccc4ccccc4n3)c2)cccc1C(F)(F)F

Procedure:
A solution of 2-[3-(quinolin-2-ylmethoxy)-benzyloxy]-6-trifluoromethyl-benzaldehyde (46 mg, 0.1 mmol, example 50) in 2-methyl-2-butene (1 mL), t-butanol (2 mL) and water (2 mL) is treated with sodium dihydrogenphosphate dihydrate (153 mg, 1.1 mmol) and sodium chlorite (198 mg, 2.2 mmol). After 45 min. the reaction is partioned between dichloromethane (50 mL) and water (50 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound: m.p. 184–185° C.; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, 1H), 8.12 (d, 1H), 7.82–7.75 (m, 2H), 7.66–7.55 (m, 2H), 7.42 (dd, 1H), 7.30–7.27 (m, 2H), 7.16 (d, 1H), 7.07 (dd, 1H), 6.88 (d, 1H), 6.77 (dd, 1H), 5.44 (s, 2H), 5.07 (s, 2H); MS (ESI) 454 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:10][CH:9]=1.[OH-].[K+].N#[N+][O-]>CCOCC.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:13]=1
Reactant: O=C(O)CCCCc1ccc(F)cc1
Agent: N#[N+][O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCCCCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (0.27 g, 7.1 mmol) in dry Et2O (6 mL), 5-(4′-fluorophenyl)valeric acid (0.35 g, 1.8 mmol) in dry Et2O (5 mL) was added dropwise. The mixture was left to react at room temperature for 4 hrs, then at 0° C. H2O (0.35 mL), 3M KOH solution (0.35 mL) and N2O (1 mL) were very slowly added. The mixture was stirred for 1 hr at 0° C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness affording the title compound (0.32 g, 97%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.34-1.47 (m, 2H), 1.55-1.72 (m, 4H), 2.49-2.68 (m, 2H), 3.64 (t, J=6.56 Hz, 2H), 6.86-7.03 (m, 2H), 7.06-7.17 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:24]=[N:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Reactant: BrCc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1sc(Br)cc1NCc1cccnc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (100 mg, 1.51 mmol), 3-(bromomethyl)pyridine hydrobromide (457 mg, 1.81 mmol), cesium carbonate (1.72 g, 5.29 mmol) and DMA (15 mL) was stirred at 80° C. for 2 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (5 mL). To the solution were added potassium carbonate (500 mg) and water (2.5 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 50:50 hexane/EtOAc) to give the title compound (260 mg, 53%) as a yellow solid:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].[CH2:17](Br)[CH:18]=[C:19]([CH2:21][CH2:22][CH:23]=[C:24]([CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH3:25])[CH3:20]>CN(C)C=O>[C:12]([CH:11]([P:6](=[O:7])([O:5][CH2:3][CH3:4])[O:8][CH2:9][CH3:10])[CH2:17]/[CH:18]=[C:19](\[CH3:20])/[CH2:21][CH2:22]/[CH:23]=[C:24](\[CH3:25])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C/C=C(\C)CC/C=C(\C)CCC=C(C)C)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
0.59 g of 55% sodium hydride was suspended in 5 ml of N,N-dimethylformamide in a nitrogen atmosphere, followed by the dropwise addition thereto of 5 ml of a solution of 3.0 g of ethyl diethylphosphonoacetate in N,N-dimethylformamide at room temperature. The obtained mixture was stirred for 10 minutes. 5 ml of a solution of 4.5 g of farnesyl bromide in N,N-dimethylformamide was added to the resulting mixture at room temperature. The obtained mixture was further stirred for one hour, followed by the addition thereto of ice-water. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The obtained crude product was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to give 2.6 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH2:47].CCN(CC)CC>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: COCCOCCOCCOCCN
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCCOCCOCCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 28.3 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.210 g, 0.429 mmol) by treatment with 2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethylamine [CAS-no. 85030-56-4] (0.089 g, 0.429 mmol) and Et3N (0.180 mL, 1.287 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc gave the title compound (0.080 g, 28%) as an orange oil. MS (ISP) 659.7 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:23]=[N+:24]=[N-:25])=O)=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:23]([CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1)=[N+:24]=[N-:25]
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
A 25 mL flask was charged with (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (287 mg, 1.50 mmol), tetrahydrofuran (5 mL) and diphenylphosphonic azide (356 μL, 1.65 mmol), purged with nitrogen, and cooled in ice. A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (236 μL, 1.57 mmol) in THF (1 mL) was added dropwise to the resultant mixture, and after 1.5 h, the mixture was warmed to room temperature and stirred overnight. Additional diphenylphosphonic azide (100 μL, 0.3 equiv.) was added followed by additional 1,8-diazabicyclo[5.4.0]undec-7-ene (90 μL, 0.4 equiv.), and the mixture was again stirred overnight. The reaction was quenched with 1M NaOH (20 mL), and poured into chloroform (20 mL). The organic layer was washed with 1M Na2HPO4 (pH 8, 2×15 mL), dried (Na2SO4), filtered and concentrated to a yellow oil which was purified by silica gel column (0-25% ethyl acetate/hexane) to yield a colorless oil (301 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:13]([C:11]2[C:10]([CH3:16])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]1)#[N:24]
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(N2CCC(O)CC2)c(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.7 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.0 g), 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (1.0 g), 1-hydroxybenzotriazole (0.7 g) and 1-ethyl-3-(3′dimethylaminopropyl)carbodiimide (1.0 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 5 h. The reaction mixture was treated with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase:chloroform:methanol=100:1). Diisopropyl ether was added to the obtained oily substance to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give the title compound (0.7 g), melting point: 224–225° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C1([O:21][C:22]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:22]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(OC2CCNCC2)cc1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
2.7 g (7.58 mmol) of 4-[(4-bromophenyl)-oxy]piperidine, prepared in Step 4.2., and 1.70 g (7.6 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}acetate, prepared in accordance with Example 1.1, are mixed in 40 ml of toluene and the solution is heated at 50° C. for 20 hours. After cooling, it is evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 40/60 mixture of ethyl acetate and cyclohexane. The eluate is subsequently triturated in diisopropyl ether, to give 2.9 g of product in powder form.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:38]=[CH:37][C:16]([CH2:17][C:18]23[C:26](=[O:27])[N:25]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:24](=[O:36])[N:23]2[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=1)=[O:4].[BH4-].[Na+]>CCOC(C)=O.O>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]23[C:26](=[O:27])[N:25]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:24](=[O:36])[N:23]2[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:37][CH:38]=1)=[O:4]
Reactant: COC(=O)C=Cc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reaction time: 1 h
Yield: 63.5 %

Procedure:
NiCl2.6H2O (0.17 g) was added to a solution of 6-[4-[2-(2-methoxycarbonylvinyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.196 g). NaBH4 (0.14 g) was added portionwise to the mixture and the mixture was stirred for 1 hour. The mixture was diluted with EtOAc and water and filtered through Celite. The organic layer was separated and washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/4, Chromatotron) afforded the titled compound (0.125 g). MS (m/z) 573 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([NH:22][CH2:23][C@H:24](O)[CH3:25])(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[NH2:22][CH2:23][C@H:24]([N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1)[CH3:25]
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (1.45 g, 7.13 mmol) was reacted with N-Boc-(R)-1-amino-2-propanol (1.50 g, 8.56 mmol) in the presence of triphenylphosphine and DIAD using the method of Example 99. After Boc-deprotection 843 mg (45%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.43 (d, 3H), 3.53-3.67 (m, 1H), 4.29-4.38 (m, 1H), 4.69-4.83 (m, 1H), 6.96 (d, 1H), 7.89 (d, 1H), 7.95 (dd, 1H), 7.97 (dd, 1H), 8.10-8.12 (m, 1H). m/z [260.7+1].
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]([CH2:11][OH:12])[CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH:3]1[CH2:4][N:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1][CH2:2]1)(=[O:23])=[O:22]
Reactant: OCC1CCC2CCCCN2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCC2CCCCN2C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 90.7 %

Procedure:
Octahydro-2H-quinolizin-3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford octahydro-2H-quinolizin-3-ylmethyl methanesulfonate as an orange oil (796 mg, 3.22 mmol, 91% yield). MS (EI) for C11H21NO3S: 248 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH:7]([NH:14][S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[N+:31]([O-:49])[CH:32]=[C:33]([Cl:48])[C:34]=1[CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)O.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[CH:7]([NH:14][S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([O:23][C@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)[CH2:35][C:34]1[C:33]([Cl:48])=[CH:32][N+:31]([O-:49])=[CH:30][C:29]=1[Cl:28])=[O:22])(=[O:17])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: CC(C)(C)OC(=O)C(NS(=O)(=O)c1cccc(C(=O)O)c1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)c3ccccc3)c2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
3-[(2-tert-Butoxy-2-oxo-1-phenyl-ethyl)sulfamoyl]benzoic acid (1.216 g, 3.11 mmol) was added to a stirred suspension of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (1.07 g, 3.11 mmol) in N,N-dimethylformamide (12 mL). To the resultant solution was added N,N-4-(dimethylamino)pyridine (0.189 g, 1.55 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.192 g, 6.22 mmol) and the reaction was stirred at room temperature for 18 hours. After this time, the reaction mixture was concentrated under reduced pressure and water (30 mL) was added; the resulting off-white precipitate was filtered and dried in air. The crude material was purified over a 50 g silica cartridge on an ISOLERA system; eluting initially with iso-hexane with an increasing solvent gradient to 100% ethyl acetate over four column volumes, after which 100% ethyl acetate was maintained for six column volumes. The desired fractions were combined and concentrated under reduced pressure to yield the title product as a white solid (1.340 g, 60%).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH:5]([CH3:8])[CH2:4][S:3]1.OO.[CH3:11][OH:12]>>[CH3:1][C:2]1([O:12][CH3:11])[C:6](=[O:7])[CH:5]([CH3:8])[CH2:4][S:3]1
Reactant: CC1CSC(C)C1=O
Reactant: CO
Agent: OO
Product: COC1(C)SCC(C)C1=O

Procedure:
To a solution of 411 g (3.16 mol) of 2,4-dimethyl-tetrahydro-thiophen-3-one in 3000 ml of methanol are added dropwise, at an internal temperature of 63°-65° and over a period of one hour, 256.4 g (2.70 mol) of 35.8% hydrogen peroxide.