Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:57][CH3:58])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:51][Si](C)(C)C)[CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:40]([CH3:56])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:59])=[CH:25][CH:24]=1.O>O1CCCC1>[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:51])[CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:40]([CH3:56])[CH:39]=3)[CH2:57][CH3:58])=[CH:31][C:30]=2[CH3:59])=[CH:27][CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.094 mL, 0.094 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 52-(1); 36.5 mg, 0.063 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for two hours. The reaction mixture was then poured into water, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (25 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[CH2:31]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:40][O:41][C:42]1[CH:61]=[CH:60][C:45]([C:46](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:44][CH:43]=1.CO>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][O:37][C:46]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:45]3[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:61][CH:60]=3)[C@@H:32]([OH:33])[CH2:31]2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](CO)O2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Yield: 71.9 %

Procedure:
Compound 6 (0.62 g, 1.24 mmol) in dry pyridine (25 mL) was treated with 4-monomethoxytrityl chloride (0.46 g, 1.49 mmol) at room temperature for 16 h. After addition of methanol (5 mL), the mixture was concentrated to dryness. The residue was dissolved in dichloromethane (60 mL) and washed successively with water (40 mL), a saturated aqueous solution of NaHCO3 (40 mL) and water (3×40 mL). The organic layer was dried, filtered, concentrated and co-evaporated with toluene and methanol. The residue was purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to give 7 (0.71 g, 72%) as a foam: 1H NMR (DMSO-d6): δ 2.21 (d, 1H, H-2′ J2′,2″=14.3 Hz), 2.6-2.7 (m, 1H, H-2″), 3.1-3.3 (2m, 2H, H-5′ and H-5″), 3.64 and 3.65 (2s, 6H, 2×OCH3), 4.1-4.2 (m, 1H, H-4′), 4.2-4.3 (m, 1H, H-3′), 5.68 (d, 1H, OH-3′, JH,OH=5.2 Hz), 6.24 (d, 1H, H-1′, J1′,2″=7.0 Hz), 6.7-6.8 and 7.1-7.3 (2m, 29H, 2 MMTr and NH-6) 7.83 and 8.21 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 796 [M+H]+, 408 [BH2]+, (FAB−) m/z 794 [M−H]−, 406 [B]−; UV (95% ethanol): λmax 275 nm (ε 30900), λmin 246 nm (ε 12800); [α]D20=+14 (c 1.03, DMSO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:17]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[Cl:25][CH2:26][C:27]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH:8]2[CH2:7][C:6]3[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:9]2)[CH2:16][CH2:15]1)=[O:28]
Reactant: Clc1ccc2c(c1)CC(CN1CCNCC1)O2
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(CC2Cc3cc(Cl)ccc3O2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a solution of 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (1.3 g, 5.1 mmol) in dichloromethane (50 ml) was added triethylamine (782 mg, 7.73 mmol, 1.5 eq) and 2-chloroacetyl chloride (758 mg, 6.71 mmol, 1.3 eq) dropwise with stirring at 0° C. for 1 hour at room temperature. The reaction mixture was quenched by the addition of water (80 ml) and extracted with dichloromethane (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 3% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one as yellow oil (1.0 g, 59%); (ES, m/z): [M+H]+ 329; 1H NMR (300 MHz, CDCl3): δ 7.04-7.12 (m, 2H), 6.69 (d, J=8.4 Hz, 1H), 4.95-5.08 (m, 1H), 4.11 (s, 2H), 3.56-3.73 (m, 5H), 3.23-3.32 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.91-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (dd, J=7.8 Hz, 13.5 Hz, 1H), 2.48-2.75 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[C:14]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[C:11]=2[OH:32])=[C:4]([N+:33]([O-])=O)[CH:3]=1.[N+](C1C=CC=CC=1N=NC1C=C(C(CC(C)(C)C)(C)C)C=C(C(CC(C)(C)C)(C)C)C=1O)([O-])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][N:9]([C:10]3[CH:15]=[C:14]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[C:11]=3[OH:32])[N:33]=[C:4]2[CH:3]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)CC(C)(C)C)c1
Agent: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC(C)(C)C)c1
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)CC(C)(C)C)c1
Yield: 71.8 %

Procedure:
When, using the general procedure of Example 2, the amount of 4-chloro-2-nitro-2'-hydroxy-3',5'-di-tert-octylazobenzene was substituted for 2-nitro-2'-hydroxy-3',5'-di-tert-octylazobenzene, the above-named compound was prepared in a yield of 71.8% as pale yellow crystals melting at 121°-122° C. (Compound 2)
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.CCN(C(C)C)C(C)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>C(Cl)Cl>[S:1]1[C:5]([CH2:6][CH2:7][O:8][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OCCc1cc2ccccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of 2-benzo[b]thiophen-2-yl-ethanol (16.8 mmol) in CH2Cl2 (60 mL) were added DIPEA (33.6 mmol) and mesylchloride (20.2 mmol.) The mixture was stirred for 18 hrs at RT, diluted with CH2Cl2, washed with sat. NaHCO3 (3×), brine (1×), dried (MgSO4) and concentrated in vacuo to give 4.3 g (99%) of methanesulfonic acid 2-benzo[b]thiophen-2-yl-ethyl ester which was used in the next step without further purification.
Reaction SMILES: [Cu][C:2]#[N:3].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13](Br)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(OCC)(=O)C>CN1CCCC1=O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([C:2]#[N:3])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Br)c(C(C)C)cc1OC
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(C#N)c(C(C)C)cc1OC
Temperature: 0 °C
Yield: 74.8 %

Procedure:
Copper (I) cyanide (550 mg, 6 mmol) was added to a solution of methyl 2-methoxy-5-bromo-4-iso-propylbenzoate (861 mg) in N-methyl-2-pyrolidinone (30 ml). The mixture was stirred under argon and boiled under reflux for 4 h. The mixture was cooled, poured into excess ice/water and ethyl acetate and filtered. The organic phase was separated, washed with water, brine and dried(MgSO4). Evaporation gave a crude brown solid which was purified by chromatography on silica gel eluting with ethyl acetate/n-hexane (1:4). The product was obtained as a white solid (523 mg).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6](N(OC(C)C(O)C)OC(C)C(O)C)=[C:5](CCC)[CH:4]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.C1(P(Cl)(Cl)=O)C=CC=CC=1.[CH2:50]([O:54][CH2:55][CH:56]1[CH2:63][N:62]([C:64]2[CH:69]=[CH:68][C:67]([O:70][CH2:71]CCCCCCCCCCC)=[CH:66][CH:65]=2)[CH2:61][CH:60]([CH2:83][O:84][CH2:85][CH2:86][CH2:87][CH3:88])[O:59][P:58](=[O:95])(C2C=CC=CC=2)[O:57]1)[CH2:51][CH2:52][CH3:53]>ClCCl>[CH2:50]([O:54][CH2:55][CH:56]1[CH2:63][N:62]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH3:71])=[CH:68][CH:69]=2)[CH2:61][CH:60]([CH2:83][O:84][CH2:85][CH2:86][CH2:87][CH3:88])[O:59][P:58](=[O:95])([O:2][C:3]2[CH:21]=[CH:20][CH:6]=[CH:5][CH:4]=2)[O:57]1)[CH2:51][CH2:52][CH3:53]
Reactant: CCCc1cc(OC)ccc1N(OC(C)C(C)O)OC(C)C(C)O
Reactant: CCCCCCCCCCCCOc1ccc(N2CC(COCCCC)OP(=O)(c3ccccc3)OC(COCCCC)C2)cc1
Agent: CN(C)c1ccccn1
Agent: O=P(Cl)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOCC1CN(c2ccc(OC)cc2)CC(COCCCC)OP(=O)(Oc2ccccc2)O1
Yield: 16 %

Procedure:
It is prepared from 4-methoxy-N,N-di(2-hydroxy-3-butoxy)-propyl aniline (1.91 g, 5 mmol), pyridine (1.2 g, 15 mmol), dimethylaminopyridine (0.2 g) and phenylphosphonic dichloride (1.1 g, 5.1 mmol) in dichloromethane as described for compound 200 to obtain a pale yellow liquid 0.4 g (16%) and its isomer 0.5 g (19% a pale yellow liquid).
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccncc1)N(c1ccccc1)c1ccccc1

Procedure:
Employing the general method of Example 1, 27.5 g (0.12 mol) of diphenylcarbamic chloride and 20 g (0.12 mol) of 4-aminopyridine were heated under reflux for two hours in 150 ml of chloroform containing 12.0 g (0.12 mol) of triethylamine to produce the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.F[P-](F)(F)(F)(F)F.[N:21]1([O:30][C:31](N(C)C)=[N+](C)C)[C:25]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:21]([O:30][CH3:31])[CH3:25])=[O:13])[NH:6]2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2c(Cl)cccc2[nH]1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2c(Cl)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.8 %

Procedure:
A mixture of 4-chloro-1H-indole-2-carboxylic acid (from Ryan Scientific, 1.0 g, 5.1 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.9 g, 7.7 mmol) and triethylamine (3.6 mL, 26 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (0.75 g, 7.7 mmol) was added and the resulting suspension was stirred at room temperature overnight. The mixture was quenched with water and then extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-35% EtOAc in hexane) to give the desired product (0.35 g, 29%). LCMS calculated for C11H12ClN2O2(M+H)+: m/z=239.1. Found: 239.1.
Reaction SMILES: [C-:1]1([O:6][CH2:7][C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16].P(Cl)(Cl)[Cl:18]>N1C=CC=CC=1.C1C=CC=CC=1>[C-:1]1([O:6][CH2:7][C:8]([Cl:18])=[O:10])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16]
Reactant: O=C(O)CO[c-]1cccc1
Reactant: ClP(Cl)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)CO[c-]1cccc1
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To ferrocenyloxyacetic acid (1.56 g, 0.006 m) and pyridine (4 drops) in benzene (100 cm3) was added dropwise phosphorous (III) chloride (5.4 cm3). The mixture was stirred for 3 hours at 60° to 70° C. After this time the benzene solution was decanted and the benzene removed under vacuum. The residue was taken up in benzene and the benzene again removed under vacuum. This procedure was repeated. Recrystallization from light petroleum (40° to 60°) gave 1.40 g (83.8%) of ferrocenyloxyacetyl chloride. The chloride (1.40g, 0.005 m) was taken up in dichloromethane (5cm3) and added dropwise to a mixture of 6-aminopenicillanic acid (1.08 g, 0.005 m) and triethylamine (1.01 g, 0.01 m) in dichloromethane (25 cm3) at 0° C. The mixture was stirred for 15 minutes at 0° C. and for 1 hour at 15° C. The solution was then filtered and the solvent removed under vacuum. The residue was taken up in a mixture of water (100 cm3) and ethyl acetate (25 cm3) and the aqueous layer adjusted to pH 2.5 with 2M HCl. The layers were separated and the ethyl acetate layer washed with water, dried, filtered and a 40% solution of SEH in 4-methylpentan-2-one (2 cm3) added. Worked up as previously the yield was 1.53 (67%) of the sodium salt of 6-(2-ferrocenyloxyacetamido) penicillanic acid. I.r. spectrum showed strong β-lactam absorption at 1770 cm-1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:6]1[CH:8]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:12]#[N:13]
Reactant: CN(C)C=O
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Yield: 23 %

Procedure:
A solution of 5-chloro-2-nitro-aniline (6.902 g, 40 mmol), Zn(CN)2 (2.818 g, 24 mmol), and Pd(PPh3)4 (2.311 g, 2 mmol) in DMF (40 mL) was heated to 120° C. for 4 days. Cooled to room temperature. Partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide 1.49 g (23%) of 3-amino-4-nitro-benzonitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([CH:26]=[O:27])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CCCCCCC.C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([CH:26]([OH:27])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1ccc(C(O)C2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.2 g (11.8 mmol) 4-bromoanisole in 30 mL dry heptane under nitrogen was added 8.02 mL (1.6 M in hexane, 12.83 mmol) n-butyl lithium dropwise, and the mixture was stirred at room temperature for 30 minutes. The solution was then cooled to −78° C. and a solution of 2.0 g (10.7 mmol) 3-formyl-azetidine-1-carboxylic acid tert-butyl ester (route 18, step a) in 30 mL dry THF was added. The resultant mixture was allowed to warm to room temperature, quenched with 50 mL 1 M sodium bicarbonate and extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 4:1 to 1:1).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:11][C@@H:10]([C:12](=[O:17])[N:13]([O:15][CH3:16])[CH3:14])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:16][O:15][N:13]([CH3:14])[C:12]([C@@H:10]1[CH2:11][C@H:8]([CH2:7][C:6]([OH:18])=[O:5])[CH2:9]1)=[O:17]
Reactant: CON(C)C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)[C@H]1C[C@@H](CC(=O)O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of 2 g of cis-[3-(methoxy-methyl-carbamoyl)-cyclobutyl]-acetic acid tert-butyl ester in 25 mL of dichloromethane was added 10 mL of trifluoroacetic acid. The mixture was allowed to warm and stir for 2 h then concentrated under reduced pressure. The residue was taken up in 3×50 mL of toluene and repeatedly concentrated under reduced pressure to remove trifluoroacetic acid. Drying under vacuum overnight gave 1.6 g of product as a colorless oil: MS (m+1)=202.3; 1H NMR (400 MHz, CDCl3) 9.0 (br s, 1H), 3.62 (s, 3H), 3.18 (s, 3H), 2.65 (m, 1H), 2.5 (overlapping d and m, 3H), 2.4 (dd, 1H), 2.0 (, m, 2H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]=[C:25]=[S:26].CCOCC>C1COCC1>[CH3:23][NH:24][C:25]([NH:19][NH:18][C:16](=[S:17])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:26]
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN=C=S
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC(=S)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 8 h

Procedure:
1.62 g (5 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydrazine carbothioamide are dissolved in 30 ml of THF, 0.44 g (6 mmol) of methyl isothiocyanate are added, and the reaction mixture is left to stand overnight at room temperature. Ether is added to complete precipitation and the precipitate formed is suction filtered, washed with ether and recrystallised from ethanol. The analytical values are summarized in Table I.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=2)[N:10]=1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=2)[N:10]=1
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCOc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture comprising 20 ml of ethylene glycol monomethyl ether and 70 mg of 55% sodium hydride was heated to 100° C., followed by the addition of a mixture comprising 500 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline and 5 ml of ethylene glycol monomethyl ether. The obtained mixture was heated under reflux for 2 hours and poured into 50 ml of water. The obtained mixture was extracted with 50 ml of ethyl acetate twice. The organic layers were together washed with 70 ml of an aqueous solution of sodium chloride twice, dried over magnesium sulfate and concentrated under a reduced pressure to give a crystalline residue. This residue was reprecipitated from ethyl acetate/n-hexane to give 420 mg of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:12][C:11](=[O:13])[CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:9]2=[O:23])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[O:23]=[C:9]1[CH:8]([CH2:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:12][C:11]([O:13][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:10]1[C:14]1[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)CC(CC3CCOCC3)C2=O)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)CC(CC3CCOCC3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a solution of 4-(tetrahydro-pyran-4-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (100 mg, 0.25 mmol) in dichloromethane (5 ml) and triethylamine (140 μl, 1 mmol) is added the pivaloyl chloride (91 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethyl-propionic acid 3-oxo-4-(tetrahydro-pyran-4-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopent-1-enyl ester (102 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH2:7][CH2:6][C:5]([CH2:11][CH3:12])([CH3:10])[NH+:4]1[O-:13])[CH3:2].[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(ON1C(CC)(C)CCC(C)C1(CC)C)(=O)C>>[C:15]([O:13][N:4]1[C:5]([CH2:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:14])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCC1(C)CCC(C)C(C)(CC)[NH+]1[O-]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CCC1(C)CCC(C)C(C)(CC)N1OC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)ON1C(C)(CC)CCC(C)C1(C)CC

Procedure:
2,6-Diethyl-2,3,6-trimethylpiperidine 1-oxide (for preparation, see U.S. Pat. No. 4,131,599) is converted by a method analogous to Example A 30 using stearoyl chloride into the compound 137 which is obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH2:7][CH2:6][N:5]1[CH3:19].[H][H]>CO.[Pd]>[CH3:1][O:2][CH2:3][CH:4]1[N:5]([CH3:19])[CH2:6][CH2:7][N:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH2:16])[CH2:9]1
Reactant: COCC1CN(c2ccncc2[N+](=O)[O-])CCN1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCC1CN(c2ccncc2N)CCN1C

Procedure:
To a solution of 2-(methoxymethyl)-1-methyl-4-(3-nitropyridin-4-yl)piperazine (84 mg, 0.3.1 mmol) in methanol was added Pd on C (10%, wet, Degussa) (10 mg) and the reaction mixture was stirred overnight at room temperature under a balloon of hydrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to yield 4-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-3-amine as a film. (72 mg, 96%). MS (ES+) 267.1.