Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@:11]3([CH2:16][C@@H:15]([C:17]([OH:19])=O)[N:14]([C:20](=[O:36])[C@@H:21]([NH:26][C:27](=[O:35])[CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13]3)[O:10][C:9]2=[O:37])[CH:5]=[CH:6][CH:7]=1.[NH2:38][C@@H:39]([CH2:48][CH2:49][CH3:50])[CH:40]([OH:47])[C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@:11]3([CH2:16][C@@H:15]([C:17]([NH:38][C@@H:39]([CH2:48][CH2:49][CH3:50])[CH:40]([OH:47])[C:41]([NH:43][CH:44]4[CH2:45][CH2:46]4)=[O:42])=[O:19])[N:14]([C:20](=[O:36])[C@@H:21]([NH:26][C:27](=[O:35])[CH2:28][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:13]3)[O:10][C:9]2=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@]2(C[C@H]1C(=O)O)CN(c1cccc(Cl)c1)C(=O)O2
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 63.6 %

Procedure:
Following the procedure from Example 1 step I using (5R,8S)-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (D4) (12 mg, 22 μmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (7.3 mg, 33 μmol) gave 10 mg (14 μmol) of (5R,8S)-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxamide (E4). LC MS+/−: 702.54/700.74 at 3.68 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: Brc1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 88 %

Procedure:
Under an atmosphere of argon, 2-bromoiodobenzene (7.9 g, 25 mmole), biphenylboronic acid (5.0 g, 25 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (60 ml). To the obtained solution, an aqueous solution of sodium carbonate (8.0 g, 75 mmole, 3 eq/40 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and white needle crystals (6.8 g, 88%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:35][CH2:34]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:36]2[CH2:37][CH2:38][CH:33]([NH:32][C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:34][CH2:35]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: COc1ccc(CS(C)(=O)=O)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CS(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(methylsulfonylmethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[CH3:26])[CH:18]=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].[Cs+]>CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[CH3:26])[CH:18]=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CN1CCCC1c1cncc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: CN1CCCC1c1cncc(-c2ccc(O)cc2)c1
Yield: 92.5 %

Procedure:
The above-described pyridine derivative (750 mg, 2.04 mmol) was dissolved in methanol (40 mL) and cesium fluoride (620 mg, 4.08 mmol) was added. The stirred mixture was heated at reflux for 18 h under inert atmosphere. After cooling the solvent was removed in vacuo and the resulting oil was dissolved in ethyl acetate (50 mL). This was washed with water (20 mL), brine (20 mL), dried (MgSO4) and concentrated. The crude material was chromatographed on "flash" silica gel with ethyl acetate:hexane (1:2 ) to 10% methanol: ethyl acetate as eluant to afford 5-(4-hydroxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine 480 mg, 93% as a colorless foam, 1H NMR (CDCl3, 300 MHz): δ 8.66 (d, J=2 Hz, 1 H), 8.43 (d, J=2 Hz, 1 H), 7.90 (s, 1 H), 7.32 (d, J=9 Hz, 2 H), 6.81 (d, J=9 Hz, 2 H), 3.33 (t, J=8 Hz, 1 H), 3.22 (t, J=8 Hz, 1 H), 2.41 (m, 1 H), 2.28 (s, 3 H), 2.10 (m, 2 H), 1.93 (m, 2 H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:45][N:46]=[C:47]=[O:48].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:47](=[O:48])[NH:46][CH3:45])[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CN=C=O
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Dissolve the compound of Example 3 (201 mg, 0.38 mmol) in dichloromethane (4 L) and add triethylamine (0.50 mL, 3.5 mmol) followed by methylisocyanate (500 mg, 8.7 mmol). After stirring for 30 minutes, pour the reaction mixture into saturated aqueous sodium bicarbonate and extract with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 4%) to give 130 mg of the title compound (60%): mass spectrum (ion spray): m/z=575.3 (M+H) and 518.3 (M−MeNCO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(OC)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(OC)cc1CBr
Temperature: 25 °C
Yield: 144.7 %

Procedure:
To a solution of methyl 4-methoxy-2-methylbenzoate (1 g, 5.6 mmol) in CCl4 (25 mL) was added dropwise N-bromosuccinimide (1.1 g, 6.2 mmol) previously dissolved in CCl4 (5 mL) and a catalytic amount of benzoyl peroxide. The mixture was refluxed for 2 hours, cooled to room temperature and poured onto iced water. The aqueous mixture was extracted with DCM (3×), and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo to provide 2.1 g of the titled product as light yellow solid (˜100% yield): [M+H+] m/z 260.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][CH:12](O)[CH3:13].CS(C)=[O:17]>>[CH3:10][N:11]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][OH:17]
Reactant: N#Cc1ccc(F)cc1
Reactant: CNC(C)O
Reactant: CS(C)=O
Product: CN(CCO)c1ccc(C#N)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 4-fluorobenzonitrile (5.35 g, 44.2 mmol) in DMSO (30 mL) containing excess methylaminoethanol was heated with stirring to 120° C. for 8 h. The solution was then cooled and concentrated under reduced pressure. The crude residue was partitioned between H2O/EtOAc and the organic phase then washed with water (×2), dried (Na2SO4), filtered and concentrated and percolated through a pad of SiO2 (CH2Cl2 then EtOAc elution) to give 4-(N-methyl,N-(hydroxyethyl)amino)benzonitrile (5.6 g, 72% yield) as a colourless liquid, which was used without further purification. A solution of the above nitrile (5.6 g, 31.8 mmol) and Et3N (8.8 mL, 63.6 mmol) in dry CH2Cl2 (50 mL) was treated at 0° C. with MsCl (3.0 mL, 38.2 mmol). The mixture was stirred for 20 min and partitioned between aqueous NaHCO3 /EtOAc. The organic phase was then dried (Na2SO4), filtered and concentrated under reduced pressure to yield the crude mesylate, which was treated with excess LiCl in DMF (25 mL) at 140° C. for 5 min with rapid stirring. Excess DMF was removed under reduced pressure and the residue was partitioned between H2O/EtOAc. Workup of the organic layer and chromatography of the residue on SiO2 and elution with petroleum ether/EtOAc (3:1) afforded pure 4-(N-methyl,N-(2-chloroethyl)amino)benzonitrile (3.6 g, 58% yield), mp (petroleum ether/CH2Cl2) 104.5-105.5° C. 1H NMR (CDCl3) δ 7.48 (d, J2,3 =9.1 Hz, 2 H, H-2,H-6), 6.67 (d, J2,3 =9.1 Hz, 2 H, H-3, H-5), 3.74 (complex t, J=7.3 Hz, 2 H, NCH2CH2Cl), 3.64 (complex t, J=7.3 Hz, 2 H, NCH2CH2Cl), 3.09 (s, 3 H, NCH3); 13C NMR δ 150.95, 133.66, 120.30, 111.50, 98.50, 53.77, 40.16, 39.02. Anal. (C10H11ClN2) C,H,N.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([O-:4])=[O:3].[CH:13]1([S:16](Cl)(=[O:18])=[O:17])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl.Cl.O>[CH:13]1([S:16]([NH:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)(=[O:18])=[O:17])[CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cccc(CNS(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Nitrobenzylamine HCl (1.48 g), cyclopropanesulfonyl chloride (1 g) and triethylamine (2.98 mL) were dissolved in dichloromethane (20 mL). The reaction solution was stirred at rt overnight. The reaction mixture was diluted with 1N HCl aq. solution (50 mL) and water (100 mL). The solution was extracted with ethyl acetate (2×100 mL). The organic solution was evaporated to give N-cyclopropylsulfonyl-3-nitrobenzylamine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:45])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH2:33][O:34][Si](C(C)C)(C(C)C)C(C)C)[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:45])[O:5][C:6]1[CH:22]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH2:33][OH:34])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:20]=[C:8]([O:9][C:10]2[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=2)[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=NC[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Reaction time: 2 h
Yield: 32.3 %

Procedure:
2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5R)-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulfonyl)pyrazine (496 mg, 0.82 mmol) synthesized in Example (101c) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 0.82 mL, 0.82 mmol) was added, followed by stirring for 2 hours under nitrogen atmosphere. To the reaction solution, water (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (133 mg, yield 35%) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][NH:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29].Cl[C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][C:32](=[O:33])[NH:2][CH2:3][NH:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)([C:17]([F:18])([F:19])[F:20])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 44.2 %

Procedure:
In a suspended solution of 0.13 g of N-aminomethyl-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide hydrochloride synthesized in Synthetic Example 32 in 4 ml of dichloromethane, 0.03 g of methyl chloroformate and 0.08 g of triethyl amine were added with stirring at room temperature, and stirred at room temperature for 3 hours. After the completion of the reaction, the solvent was distilled under reduced pressure, the residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.06 g of the aimed product as colorless resinous substance.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)(O)O>C(OCC)C.O1CCCC1>[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[CH2:3][CH:2]=[CH2:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CCCCCCCCCCc1ccccc1
Reactant: C=CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)CCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a cooled solution of 1M allyl magnesium bromide in diethyl ether was added dropwise, under nitrogen, a solution of 18.2 g of 10-phenyldecanal (prepared as in Step 1) in 200 ml of dry tetrahydrofuran. The reaction mixture was stirred at about 5° for 15 minutes, at room temperature for 1 hour, and then at reflux for 15 minutes. The reaction mixture was cooled to room temperature and poured into a mixture of 400 g of ice and 40 ml of 9M sulfuric acid. Upon standing the mixture separated into aqueous and organic layers. The organic layer was stirred for 15 min with solid sodium bicarbonate and then concentrated. The aqueous layer was extracted with diethyl ether (2×200 ml) and the extracts were combined with the concentrated organic layer. The combined organics were washed with water (300 ml) and a half-saturated aqueous solution of sodium chloride (300 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. High pressure liquid chromatography of the oil using 10% diethyl ether/hexane as the eluent gave 6.98 g (30%) of 13-phenyl-1-tridecen-4-ol as an oil.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:19].[OH-].[Na+].CO>C(Cl)Cl>[NH2:2][C:1]1[N:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCOC(=O)CNN
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)Cn1nc(-c2ccc(C)cc2)c(C(N)=O)c1N
Yield: 27.5 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (425 mg, 1.83 mmol), ethyl hydrazinoacetate hydrochloride (311 mg, 2.01 mmol) and sodium hydroxide (80 mg, 2.01 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 10% methanol in CH2Cl2) and was recrystallised from ethyl acetate to give the title compound as white crystals (152 mg) m.p. 179°. δH (CDCl3) 7.43 (2H, d, J 8.1 Hz), 7.26 (2H, d, J 8.1 Hz), 5.56 (2H, br s), 5.22 (2H, br s), 4.77 (2H, s), 4.27 (2H, q, J 7.2 Hz), 2.40 (3H, s) and 1.32 (3H, t, J 7.2 Hz).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].N#N.[CH2:9]1[CH2:13][O:12][CH2:11][CH2:10]1>>[CH3:1][CH:2]([CH:11]1[CH2:10][CH2:9][CH2:13][O:12]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCC
Reactant: C1CCOC1
Agent: N#N
Product: CCCCC(C)C1CCCO1
Yield: 96 %

Procedure:
3 g of 1-hexene and 22 g of THF were passed into the reactor tube with a 30 ml/min flow of N2. The reaction mixture was washed with 150 ml of 1:1 v/v water/ether to separate the 1 g. of water soluble THF dimer 2-(1-methyl-pentyl)-tetrahydrofuran which was formed. The organic phase was chromatographed on silica gel. Elution with 5% ether and 5% petroleum ether in cyclohexane to yield material which was shown to be 96% pure title compound by GC. 250 MHz 13C-NMR (CDCl3 ; data for d,l for meso mixture): 13.88 (q, 2C), 14.84 (q, IC), 15.40 (q, IC), 22.73 (t, 2C), 25.65 (t, lC), 25.75 (t, IC), 28.39 (t, lC), 28.74 (t, lC), 29.00 (t, IC), 29.15 (t, IC), 32.54 (t, IC), 33.13 (t, IC), 37.66 (d, 2C), 67.52 (t, 2C), 83.60 (d, 2C).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][OH:14]>C1C=CC=CC=1>[OH:14][N:13]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: NO
Reactant: O=C(O)C(=O)c1cccc(O)c1
Solvent: c1ccccc1
Product: O=C(O)C(=NO)c1cccc(O)c1
Reaction time: 0.42 h

Procedure:
A mixture of 3-hydroxyphenylglyoxylic acid (3.32 g.) and 1 N-methanol solution of hydroxylamine (45 ml.) was refluxed with stirring, for 25 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in 1 N-sodium hydroxide aqueous solution (50 ml.) and the solution was washed with ether, acidified with hydrochloric acid under cooling and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, dried and concentrated to give yellow oil. To the oil was added benzene and benzene was distilled off. The residue was crystallized with petroleum ether and the crystals were collected by filtration, washed with petroleum ether and dried to give 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture of syn and anti isomer) (2.9 g.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A colourless solution of (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (660 g; J. Org. Chem. (2003), 68, 3923-3931) in DCM (6.6 l) was cooled down to 0° C. and treated with TEA (510 ml) and, dropwise, with pivaloyl chloride (378 ml). The reaction mixture was stirred for 24 h at rt. The reaction mixture was cooled to −8° C. and treated with DIPEA (1506 ml). A solution of sulfur trioxide pyridine complex (1036 g) in DMSO (4 l) was added dropwise over 90 min. The reaction mixture was stirred at 0° C. for 1 h and was quenched with the addition of water (41). The aq. layer was extracted with Et2O/Hex (1:1; 2×1 l) and the combined org. layers were concentrated in vacuo. The residue obtained after work up (Et2O/Hex 1:1) was crystallized from Hex (2 l) affording 675 g (74%) of a colourless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:13]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:21])[CH:6]=[C:5]2[Cl:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc2nccc(Cl)c2c1
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(Cl)c2cc(NCc3ccccc3)ccc2n1

Procedure:
6-Amino-4-chloroquinoline (0.1 g; see step (ii) above), benzaldehyde (0.055 g) and sodium tnacetoxyborohydride (0.22 g) in 1,2-dichloroethane was stirred overnight. The mixture was diluted with dichloromethane and washed with water then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and pentane. The desired fractions were concentrated and the sample evaporated to dryness to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:14])[CH3:13])[CH3:5].C(N(CC)CC)C.[F:22][CH:23]([F:33])[C:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]([CH3:32])[N:25]=1>ClCCl>[CH3:1][O:2][N:3]([CH:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:13])[CH3:14])[CH3:5])[C:29]([C:28]1[C:24]([CH:23]([F:33])[F:22])=[N:25][N:26]([CH3:32])[CH:27]=1)=[O:30]
Reactant: CONC(C)C1CCC(C)=CC1(C)C
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)C1CCC(C)=CC1(C)C
Temperature: 24 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a stirred solution of O-methyl-N-[1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethyl]-hydroxylamine (diastereomer A), prepared as described in example P7, (88 mg; 0.45 mmol) and triethylamine (75 μl; 0.54 mmol) in dichloromethane (2 ml) was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (87 mg; 0.45 mmol). The reaction mixture was stirred at 24° C. for 16 h under nitrogen atmosphere. The mixture was concentrated to an oil which was subject to flash-master column chromatography (elution gradient: cyclohexane/ethyl acetate 99:1 to 1:99) to afford 106 mg (66% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethyl]-amide as an amorph solid.