Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[NH2:14])=O.CN.[C:17]([Cu])#[N:18]>>[CH3:17][NH:18][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[NH2:14])=[O:2]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc2c(c1N)OCO2
Agent: CN
Product: CNC(=O)c1ccc2c(c1N)OCO2

Procedure:
4-Amino-benzo[1,3]dioxole-5-carboxylic acid methylamide was prepared by heating a mixture of 4-amino-benzo[1,3]dioxole-5-carboxylic acid methyl ester (198 mg, 1.01 mmol, Dallacker, Franz, et al. Justus Liebigs Ann Chem 1966, 694 117-22) with 2.0 M methanolic MeNH2 (7 mL, 14 mmol) and CuCN (1.42 g, 28.6 mmol) to 50° C. for 72 h. Excess catalyst was removed by filtration; filtrate was extracted into CH2Cl2, washed with water and dried by passing through a plug of Na2SO4. Evaporation of solvent afforded a white powder (187 mg, 95%) that was used in subsequent steps without further purification.
Reaction SMILES: O=[O+][O-].[Si:4]([O:11][CH2:12][CH2:13][C@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:15](C)=[CH2:16])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCC.CC[O:52]CC>O=O.ClCCl>[Si:19]([O:18][C@@H:14]([CH2:13][CH2:12][O:11][Si:4]([C:7]([CH3:8])([CH3:9])[CH3:10])([CH3:5])[CH3:6])[C:15](=[O:52])[CH3:16])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21]
Reactant: C=C(C)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CCOCC
Agent: O=O
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: CC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 70 %

Procedure:
Ozone in O2 is directed at -78° C. through a solution of 1.610 g (4.67 mmol) of 11 in 200 ml of absolute dichloromethane (dry ice/acetone-cold bath). When starting compound 11 can no longer be detected by thin-layer chromatography in the solution, 3.89 g (14.83 mmol) of triphenylphosphine is added, and the cold bath is removed. The reaction batch is allowed to come slowly to room temperature, and the solvent is distilled off in a vacuum. Flash chromatography of the residue by a silica gel column with pentane/Et2O (50:1) yields 1.135 g (3.27 mmol, 70%) of 12.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].Br[CH:11]([CH2:17]Br)[C:12]([O:14]CC)=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:8][C:4]1[C:3]2[O:9][CH2:12][CH2:11][NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1.[CH3:17][CH2:11][C:12]([O-:14])=[O:13]
Reactant: Nc1cccc(F)c1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)[O-]
Product: Fc1cccc2c1OCCN2

Procedure:
A mixture of 2-amino-6-fluorophenol (2 g, 8.3 mmol), of ethyl 2,3-dibromopropionate (1.46 mL, 9.96 mmol) and of K2CO3 (3.44 g, 24.9 mmol) in acetone (80 mL) is heated under reflux for 9 h 15 min. The mixture is cooled and filtered. The filtrate is vacuum concentrated, the residue dissolved in iced aqueous NaOH solution (1N, 10 mL) and extracted with ethyl ether. The ethereal phase is washed in water then saline water, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by filtering though silica gel using dichoromethane as eluting solvent. The title compound is obtained in oil form (1.1 g, 59%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)[CH2:29][N:28]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)[CH2:29][N:28]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(/C=C/c1ccc(F)cn1)N1C(=O)OC[C@H]1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cn1
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cn1
Reaction time: 18 h

Procedure:
To a solution of the compound (8.26 g) obtained in step 4 in dichloromethane (100 mL) were added at room temperature N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (9.6 g) and trifluoroacetic acid (0.58 g), and the mixture was stirred at 18 hr. The mixture was diluted with water (200 mL), extracted with dichloromethane (2×200 mL), dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (25% ethyl acetate/hexane) to give (4R)-4-benzyl-3-{[(3S,4S)-1-benzyl-4-(5-fluoropyridin-2-yl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one (less polar product, 11.8 g, 47%) as a yellow oil, and (4R)-4-benzyl-3-{[(3R,4R)-1-benzyl-4-(5-fluoropyridin-2-yl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one (more polar product, 10.5 g, 41%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15](=[O:17])[NH:25][CH2:24][C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccnc1
Reactant: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CO[C@@H]1C[C@@H](C(=O)NCc2cccnc2)N(C(=O)OC(C)(C)C)C1

Procedure:
The title compound is prepared analogously as described in example 14 step B using (2S,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester instead of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and 3-picolylamine instead of 4-methoxyphenethylamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[O:25][CH2:26][C:27]#[N:28])[C:19]([Cl:33])=[CH:18][N:17]=1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[O:25][CH2:26][C:27]#[N:28])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CC1(C)CCCOc2c(N)cccc21
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CC1(C)CCCOc2c(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cccc21

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and [2-(2,5-dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile in an analogous manner to Example 179 heating at 130° C. Product was isolated as a white solid (26 mg, 34%). LCMS (m/e) 450 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.58 (broad s, 1H), 8.15 (s, 1H), 8.08 (d, 1H, J=8.1 Hz), 7.93 (s, 1H), 7.55 (d, 1H, J=7.6 Hz), 7.19 (m, 2H), 7.03 (d, 1H, J=8.34 Hz), 6.97 (m, 2H), 4.88 (s, 2H), 4.02 (m, 2H), 2.01 (m, 2H), 1.67 (m, 2H), 1.37 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4][O:3]1.CNN>ClCCl>[CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([O:8][NH2:9])[CH2:4][O:3]1
Reactant: CC1(C)OCC(ON2C(=O)c3ccccc3C2=O)CO1
Agent: CNN
Solvent: ClCCl
Product: CC1(C)OCC(ON)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a stirring solution of the product of Example 33, Step A, 2-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-isoindole-1,3-dione (1.72 g, 6.20 mmol), in dichloromethane (15 mL) at 0° C. under nitrogen was added methylhydrazine (0.36 mL, 6.82 mmol) and allowed to warm to room temperature. After stirring for 2 hours the reaction mixture was concentrated in vacuo and charged with diethylether. The solids were filtered off and the filtrate was collected and concentrated to afford O-(2,2-dimethyl-[1,3]dioxan-5-yl)-hydroxylamine as a yellow oil (0.97 g, 100%). 1H NMR (400 MHz; DMSO-d6) δ 5.98 (bs, 2 H), 3.84-3.87 (m, 2 H), 3.66-3.68 (m, 2 H), 3.30-3.35 (m, 1 H), 1.29 (s, 3 H), 1.22 (s, 3 H); MS (APCI+)=147.9.
Reaction SMILES: C[N:2](C)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:12])=O.NC1N=[C:20]2[CH2:22][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:24]CC2C(=O)N=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH2:26]([N:23]1[CH2:22][CH2:20][C:6]2[C:5](=[CH:4][C:3]([NH2:2])=[CH:8][C:7]=2[Cl:12])[CH2:24]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)c1ccccc1
Reactant: NC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1cc(Cl)c2c(c1)CN(Cc1ccccc1)CC2
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 83.6 %

Procedure:
N,N-Dimethylaniline (1.4 g, 11.4 mmol) and phosphorus oxychloride (14 g, 91.2 mmol) were added to the solution of 2-amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one (2.9 g, 11.4 mmol) in 1,2-dichloroethane (23 mL, anhydrous) and were stirred in a preheated oil bath at 90° C. for 45 min. The reaction mixture was poured into ice, neutralized by solid sodium carbonate, extracted by ethyl acetate, and the dark brown semi solid was dissolved in methanol. The combined ethyl acetate and methanol solution was dried over sodium sulfate. Solvent was removed in vacuo and product was obtained as a light brown solid (2.6 g, 83%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O.CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC(=O)COc1ccc(Br)cc1
Reaction time: 0.42 h
Yield: 68 %

Procedure:
A solution of 50% (w/w) NaOH in water (188 mL) in DMSO (800 mL) was stirred at room temperature until a precipitate formed, treated dropwise with a solution of 4-bromophenol (101.2 g) in DMSO (200 mL) over 25 minutes, stirred for 25 minutes, treated with ethyl 4-chloro-3-oxobutanoate (102.2 g) over 40 minutes, adjusted to pH 3 with 6M HCl, treated with water (200 mL) over 12 minutes, stirred for 5 hours, treated with water (150 mL) over 20 minutes, and filtered. The solid was washed with sequentially with water and 40% ethanol/water and dried under vacuum (100 mm Hg) at 50° C. with a nitrogen bleed to provide 119.8 g of the desired product. 1H NMR (300 MHz, CDCl3) δ7.40 (m, 2H), 6.79 (m, 2H), 4.65 (s, 2H), 4.20 (q, 2H, J=7 Hz), 3.62 (s, 2H), 1.26 (t, 3H, J=7Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[C:24]([C:34](Cl)=[O:35])=[N:25][N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1>>[CH3:22][C:23]1[C:24]([C:34]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:35])=[N:25][N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)Cl
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1nn(-c2ccccc2)nc1C(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 58 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride and conditions outlined in procedure N. M.p.=275-280° C.; 300 MHz 1H NMR (CDCl3) δ 8.07 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 2H), 7.80 (d, J=7.5 Hz, 1H), 7.68 (t, J=8.4 Hz, 1H), 7.48 (m, 3H), 7.37 (m, 1H), 4.65 (m, 2H), 3.67 (t, 1H), 3.39 (m 1H), 3.01 (s, 2H), 2.57 (s, 3H), 2.30 (brm, 2H), 1.96 (m, 2H); LCMS: 487 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH2:14]O)[S:11][N:10]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:17].O>C1(C)C=CC=CC=1>[Br:17][CH2:14][C:12]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:13]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(-c2nsc(CO)n2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nsc(CBr)n2)cc1
Temperature: 120 °C
Yield: 58 %

Procedure:
To a solution of [3-(4-methoxyphenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.07 g, 0.29 mmol) in toluene (10 ml) was added PBr3 (0.041 ml, 0.43 mmol) and the resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.048 g, 53%).
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[C:16]([C:18]1([C:25]2[C:30]3[N:31]=[C:32]([CH:34]([CH3:36])[CH3:35])[O:33][C:29]=3[C:28]([O:37][CH3:38])=[CH:27][CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)#[N:17]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH:34]([C:32]1[O:33][C:29]2[C:28]([O:37][CH3:38])=[CH:27][CH:26]=[C:25]([C:18]3([C:16]#[N:17])[CH2:23][CH2:22][C:21](=[C:3]4[S:8][CH2:7][CH2:6][CH2:5][S:4]4)[CH2:20][CH2:19]3)[C:30]=2[N:31]=1)([CH3:36])[CH3:35]
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)c2nc(C(C)C)oc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2(C#N)CCC(=C3SCCCS3)CC2)c2nc(C(C)C)oc12
Temperature: -70 °C

Procedure:
2-Trimethylsilyl-1,3-dithiane (2.1 ml, 11.01 mmol) is dissolved in absolute THF (56 ml) and cooled to −70° C. with stirring. A solution of n-butyllithium in n-hexane (6.9 ml, 11.1 mmol of a 1.6 molar solution) is then slowly added dropwise under a nitrogen atmosphere by means of a glass syringe and the mixture is stirred at −45° C. for a further 30 min. After cooling to −70° C. again, a solution of 4-cyano-4-(2-isopropyl-7-methoxybenzoxazol-4-yl)cyclohexanone (1.5 g, 4.80 mmol, compound 3) in absolute THE (33 ml) is slowly added dropwise. The mixture is stirred at −70° C. for 1 h and then slowly warmed to RT (about 2 h). For working-up, the reaction solution is diluted with ethyl acetate (80 ml) and extracted (2 times) with 0.1 N hydrochloric acid (80 ml). The organic phase is dried using magnesium sulfate, filtered off and concentrated in vacuo. Column chromatography affords the title compound (1.34 9) as a colorless solid. TLC, silica gel (glass plates), petroleum ether/ethyl acetate (85:15), Rf=0.6.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[C:9]3[N:10]([C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH2:3]1.[OH-].[Li+].Cl>C1COCC1.CO>[F:24][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[C:9]3[N:10]([C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH2:3]1
Reactant: CCOC(=O)c1c(C)nc2c(OCC3CC(F)(F)C3)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCC2CC(F)(F)C2)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.39 g (7.06 mmol) of ethyl 8-[(3,3-difluorocyclobutyl)methoxy]-2,6-dimethylimidazo[1,2-a]-pyridine-3-carboxylate Example 106A were dissolved in 151 ml of THF/methanol (5:1), 35.3 ml (35.3 mmol) of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at RT for 2 d. The reaction mixture was acidified with 1 N aqueous hydrochloric acid solution to pH 4 and concentrated. The solid was filtered off, washed with water and dried under high vacuum. This gave 1.63 g (71% of theory; purity 95%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]([OH:18])[CH3:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]([O:18][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH3:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)[C@H]1CC[C@H](COCc2ccccc2)CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](COCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
In 50 ml of dry dimethyl sulfoxide were dissolved 2.0 g of trans-4-benzyloxymethyl-1-(1-hydroxyethyl)cyclohexane, and 2.24 ml of triethylamine and 1.88 g of t-butyldimethylsilyl chloride were added thereto with stirring at room temperature, and the mixture was stirred at room temperature for 2 hours and 50 minutes. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed successively with an aqueous citric acid solution, an aqueous sodium chloride solution, an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=50/1) to obtain 2.76 g of the desired compound as a colorless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[C:28]([N:2]2[CH2:3][CH:4]([C:6]3[CH:15]=[CH:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]=3)[CH2:5]2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: Clc1nccnc1Cl
Reactant: c1ccc2nc(C3CNC3)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccnc1N1CC(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 56.8 %

Procedure:
To a solution of 2-azetidin-3-yl-quinoline hydrochloride (1.70 g, 7.75 mmol) in DMF (30 mL) at room temperature was added Cs2CO3 (5.2 g, 16 mmol) and 2,3-dichloro-pyrazine (1.3 g, 9.0 mmol). The reaction mixture was heated to 90° C. overnight and then diluted with water (60 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (60 mL) and brine (60 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.30 g, 4.4 mmol, 58% yield) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:19]([F:22])([F:21])[F:20])[C:3]=1[NH2:4].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24]>>[I:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])[CH:6]=[C:5]([C:19]([F:20])([F:21])[F:22])[C:3]=1[NH:4][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=1
Reactant: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1

Procedure:
According to the method of 4-3 of Example 4, a target compound was prepared from 2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline and 3-nitrobenzoyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CC(O)=O>[Br-:13].[CH2:14]([N+:1]1[CH:2]=[CH:3][CH:4]=[C:5]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:6]=1)[CH2:15][CH2:16]/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CN1CCC[C@H]1c1cccnc1
Reactant: CCCCC/C=C/CCCBr
Solvent: CC(=O)O
Product: CCCCC/C=C/CCC[n+]1cccc([C@@H]2CCCN2C)c1
Product: [Br-]
Yield: 74.1 %

Procedure:
To a stirred solution of (S)-nicotine (0.47 g, 2.9 mmol) in AcOH (15 ml) was added trans-1-bromo-dec-4-ene (1.55 g, 7.08 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.82 g (74%) of (S)-trans-1-dec-4-enyl-3-(1-methyl-pyrrolidin -2-yl)-1-pyridinium bromide (NDNB-4t) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 9.71 (1H, d, J=5.7 Hz), 9.07 (1H, s), 8.40 (1H, d, J=8.1 Hz), 8.08 (1H, dd, J=8.1, 6.0 Hz), 5.42 (2H, m), 5.00 (2H, t, J=6.9 Hz), 3.54 (1H, t, J=8.4 Hz), 3.25 (1H, m), 2.44 (2H, m), 2.25 (3H, s), 1.65–2.20 (8H, m), 1.66 (1H, m), 1.15–1.40 (6H, m), 0.87 (3H, t, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 146.50, 144.36, 143.79, 143.13, 128.52, 127.15, 67.05, 61.49, 56.86, 40.70, 36.07, 32.67, 31.76, 31.56, 29.27, 29.07, 23.39, 22.70, 14.27; Anal. Calcd for C20H33BrN2.0.3H2O: C, 62.10; H, 8.76; N, 7.24. Found: C, 62.03; H, 8.88; N, 7.12.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[OH:31]/[N:30]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1

Procedure:
In analogy to example 1, step 2, from 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=391.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:30])=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1C1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.