Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[H-].[Na+].Cl[C:10]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[NH:33][C:32]4=[O:40])[CH2:27][CH2:26]3)=[CH:20][CH:19]=2)[C:15]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:14][C:11]=1[C:12]#[N:13]>CS(C)=O.O>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][O:6][C:10]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[NH:33][C:32]4=[O:40])[CH2:29][CH2:30]3)=[CH:20][CH:19]=2)[C:15]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCOc1nc(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)c(-c2ccccc2)cc1C#N
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a mixture of N,N dimethylaminoethanol in DMSO (1 mL) was added NaH (60% dispersion in mineral oil, 0.019 g, 0.481 mmol). The mixture was heated to 50° C. for 15 min. After cooling, 2-Chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (2-6, 0.050 g, 0.096 mmol) was added and the reaction was allowed to stir for 16 hr at rt. The resulting mixture was diluted with water (10 mL) and the resulting precipitate was filtered. The filtered cake was purified by reverse phase HPLC. (5% CH3CN: 95% H2O+0.01% TFA to 95% CH3CN: 5% H2O+0.01% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 10.93 (s, 1H), 9.86 (bs, 2H), 8.45 (s, 1H), 7.40-7.55 (m, 4H), 7.25-7.40 (m, 6H), 7.00 (d, J=2.93, 3H), 4.85 (t, J=4.89, 2H), 4.45 -4.55 (m, 1H), 4.34 (s, 2H), 3.64 (bs, 2H), 3.46 (d, J=11.72, 2H), 3.10-3.25 (m, 2H), 2.94 (d, J=4.15, 6H), 2.56-2.69 (m, 2H), 1.93, (d, J=12.00, 2H). HRMS m/z (M+H) Calcd: 573.2973, found: 573.2957.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O:6]([CH2:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O.CCOCC>[O:6]([CH2:13][C:14]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)CNC(=O)COc1ccccc1

Procedure:
Glycine (20 mmol) was reacted with distilled phenoxyacetyl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of water and ether as described in Example 5 Part A. The crude product was recrystallized from EtOAc (15 ml) to give title acid (2.38 gm, 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[CH:10]=1)[C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48]>CN(C)C=O.O>[OH:48][CH2:47][C:46]([NH:45][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:12]=2)[CH:10]=[C:2]([CH3:1])[CH:3]=1)([CH3:50])[CH3:49]
Reactant: CC(C)(N)CO
Reactant: Cc1cc(C(=O)O)cc(-c2cc3nccc(-c4ccccc4)c3o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NC(C)(C)CO)cc(-c2cc3nccc(-c4ccccc4)c3o2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.8 %

Procedure:
3-Methyl-5-(7-phenyl-furo[3,2-b]pyridin-2-yl)-benzoic acid (79 μmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidhydrochlorid (86,592 μmol) are dissolved in N,N-dimethylformamid (300.00 μl) and 4-methylmorpholin (157.354 μmol) and 1-hydroxybenzotriazolhydrat (86.849 μmol) are added and stirred 5 min at RT. A solution of 2-amino-2-methyl-propan-1-ol (80,000 μmol) in N,N-dimethylformamid (100.00 μl) is added. The mixture is stirred 4.5 h at RT. The reaction solution is poured into water and extracted with ethylacetate. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. The product is isolated after reversed phase column chromatography as yellow solid (33 μmol, 42% yield). HPLC (method A): Rt 2.55 min (purity 98.5%); LCMS (ESI+) (method E): Rt 2.199 min, M+H+401.1 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.60 (d, J=5.1, 1H), 8.18 (s, 1H), 8.16-8.10 (m, 2H), 7.96 (s, 1H), 7.77 (s, 1H), 7.70 (d, J=8.9, 2H), 7.65 (dd, J=14.7, 6.4, 3H), 7.58 (d, J=7.4, 1H), 4.16 (br, 1H), 3.54 (s, 2H), 2.47 (s, 3H), 1.35 (s, 6H).
Reaction SMILES: CI.NC1[CH:29]=[CH:28][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])(C)[C:10]2=O)=[C:6]([O:30][CH3:31])[CH:5]=1.[C:32](=[O:35])([O-])[O-].[K+].[K+].O.[CH3:39][N:40]([CH3:43])[CH:41]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([CH2:8][C:7]1[CH:28]=[CH:29][C:41]([N:40]([CH3:43])[CH3:39])=[CH:5][C:6]=1[O:30][CH3:31])[C:32](=[O:35])[C:11]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: COc1cc(N)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CO
Product: COc1cc(N(C)C)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
150 ml of methyl iodide are added to 238 mg of the compound of Example 48, in 4 ml of methanol and 1 ml of dimethylformamide, and 100 mg of potassium carbonate and then the reaction mixture is heated at 45° C. for 24 hours. 10 ml of water are added at room temperature and extraction is carried out with ethyl acetate. The organic phase is washed twice with water and dried over anhydrous sodium sulphate, the solvents are evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a 90/10 (v/v) cyclohexane/ethyl acetate mixture. The residue obtained is crystallized from n-pentane, filtered off and dried under reduced pressure for 4 hours; M.p.=135° C.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[C:7](=[O:15])[NH:6][C:5]=2[N:4]([CH3:16])[N:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CN(C=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:17][CH:12]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7](=[O:15])[NH:6][C:5]3[N:4]([CH3:16])[N:3]=[C:2]([CH3:1])[C:14]=3[C:13]1=2
Reactant: Cc1nn(C)c2[nH]c(=O)c3c(c12)CCCC3
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nn(C)c2[nH]c(=O)c3c(c12)C(Br)CCC3
Yield: 86.5 %

Procedure:
A solution of EXAMPLE 1 (966 mg, 4.45 mmol) in a mixture of chloroform (30 mL) and N,N′-dimethylformamide (2 mL) was treated with N-bromosuccinimide (791 mg, 4.45 mmol) and catalytic 2,2′-azobis(2-methylpropionitrile) (5 mg) at 65° C. for 18 hours. The mixture was cooled, concentrated and the residue partitioned between ethyl acetate and brine. The organic phase was washed with water, concentrated and purified by flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes to provide 1.14 g (87%) of the title compound. MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C>CN(C)C=O.[Cl-].[Li+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
2.10 g (purity 74%, 4.72 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoic acid (racemate), 780 mg (4.72 mmol) of ethyl 4-aminobenzoate, 671 mg (4.72 mmol) of Oxima and 735 μl (4.72 mmol) of DIC in 47 ml of dimethylformamide were reacted according to General Method 5B. After complete conversion, the reaction solution was diluted with 263 ml of 10% strength lithium chloride solution and 210 ml of ethyl acetate and the phases were separated. The aqueous phase was extracted twice with 210 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 100 g silica cartridge, flow rate 50 ml/min), giving the title compound. Yield: 2.1 g (75% of theory)
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1cccs1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccs2)CC1
Yield: 10.5 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound, potassium carbonate (3.0 g) and 6-bromo-1-(2-thienyl)-1-hexanone (1.6 g) were reacted and treated in the same manner as in Example 172 to give 0.27 g of 4-amino-5-chloro-N-((1-(6-oxo-6-(2-thienyl)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:34][CH:35]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC)c(F)c2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC)c(F)c2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(3-fluoro-4-methoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.4 g, 60%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[N:4]=[N:5][C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=2)[CH:8]=1.OO.CO.C(OCC)(=[O:34])C.[OH2:38]>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:27][N:2]([CH3:1])[C:3]1[N:4]=[N:5][C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15]([CH3:16])(=[O:34])=[O:38])[N:10]=2)[CH:8]=1
Reactant: CSc1nccc(-c2cc(N(C)C)nnc2-c2cccc(C(F)(F)F)c2)n1
Reactant: O
Reactant: CCOC(C)=O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CN(C)c1cc(-c2ccnc(S(C)(=O)=O)n2)c(-c2cccc(C(F)(F)F)c2)nn1

Procedure:
Compound 71 (112 mg, 0.286 mmol), sodium tungstate (10 mg, 0.02 mmol), 30% hydrogen peroxide (130 μL, 1.14 mmol), methanol (2.0 mL), and ethyl acetate (20 mL) were combined under Argon and heated to reflux for 3d. The solution was cooled, poured into water and extracted several times with ethyl acetate. The combined organic extracts were dried with anhydrous sodium sulfate. Removal of the solvent in vacuo gave 72 as a solid: 109 mg (0.259 mmol, 91%)
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:7]=1[CH:8]=O.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)(=[O:25])[CH3:24].C[O-].[Li+]>CN(C)C=O.CO.O>[OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:7]=1/[CH:8]=[CH:24]/[C:23]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1)=[O:25]
Reactant: COc1cc(OCC(CO)CO)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1cc(OCC(CO)CO)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-64B) (8.0 g, 24.8 mmol) and 4-acetylbenzenesulfonamide (4.9 g, 24.8 mmol) were dissolved in a dimethylformamide-methanol solution (170 mL, 7:3). After complete dissolution, lithium methoxide (3.8 g, 99.2 mmol) was added and the resulting red-orange slurry was stirred in the dark at room temperature for 3 h. Upon completion, as determined by HPLC, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (6×200 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (150 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 7.0 g (60%) of the title compound as a light orange solid, mp 123–124° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.25–8.29 (m, 3H), 7.90–8.11 (m, 4H), 7.66 (d, 1H, J=3.0 Hz), 7.56 (brs, 1H), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.0 Hz), 6.88 (s, 1H), 4.67 (t, 2H, J=10.8 Hz), 4.24 (d, 2H, J=6.0 Hz), 4.00 (s, 3H), 3.54–3.65 (m, 4H), 2.09–2.13 (m, 1H). MS (ESI) m/z=504 ([M+H]+, 100%). Anal. Calcd. C24H25NO7S2H2O: C, 57.24; H, 5.00; N, 2.78; S, 12.73. Found: C, 56.72; H, 5.27; N, 2.71; S, 12.11.
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24])[CH:20]=[C:19]([Cl:29])[C:18]=1[Cl:30].CCN(CC)CC.CC(=O)OCC>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([C:23]2([C:25]([F:28])([F:27])[F:26])[O:15][N:14]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=3)[CH2:24]2)[CH:20]=[C:19]([Cl:29])[C:18]=1[Cl:30]
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
To a solution of methyl 4-(chloro(hydroxyimino)methyl)-2-methylbenzoate (12.6 mmol) in DMF (30 mL) at 0° C. was added 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (4.2 g, 15.1 mmol) followed by Et3N (2.55 g, 25.2 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water (30 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1) to give methyl 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-2-methylbenzoate (4.1 g; yield 70% over 3 steps) as a pale yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.98 (d, J=8.5 Hz, 1H), 7.66 (s, 2H), 7.55 (s, 2H), 4.13 (d, J=17.5 Hz, 1H), 3.93 (s, 3H), 3.73 (d, J=17.5 Hz, 1H), 2.64 (s, 3H) ppm; MS: m/z=465.9 (M+1, ESI+).
Reaction SMILES: P([O-])([O-])([O-])=O.[CH2:6]([N:9]1[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][O:11][S@@:10]1=[O:17])[CH2:7][CH3:8].I([O-])(=O)(=O)=[O:19].[Na+]>C(OCC)(=O)C.O.[Ru](=O)=O>[CH2:6]([N:9]1[C@@H:13]([CH2:14][CH2:15][CH3:16])[CH2:12][O:11][S:10]1(=[O:19])=[O:17])[CH2:7][CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCC1CO[S@](=O)N1CCC
Agent: O=[Ru]=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC[C@H]1COS(=O)(=O)N1CCC
Yield: 93.7 %

Procedure:
Ruthenium dioxide hydrate (3 mg) and a phosphate buffer solution (pH 7.4, 28.7 mL) were subsequently added to a solution of (S)-3,4-dipropyl-1,2,3-oxathiazolidine 2-oxide (5.74 g) in ethyl acetate (46 mL) under ice-cooling and stirring. Sodium periodate (7.06 g) was added to the solution under ice-cooling and stirring, and then vigorously stirred at room temperature for 30 minutes. The suspension was filtered, and the insoluble matter was washed with ethyl acetate (17 mL). The filtrate and the washings were combined. The organic layer was separated and washed subsequently with a saturated aqueous sodium hydrogen carbonate solution (11.5 mL), an aqueous 10% sodium thiosulfate solution (11.5 mL) and a saturated aqueous sodium chloride solution (11.5 mL). Anhydrous sodium sulfate and activated carbon (0.57 g) were added to the organic layer and stirred at room temperature for 1 hour. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was added with tetrahydrofuran (8.6 mL) and concentrated under reduced pressure at 40° C. or lower to give (S)-3,4-dipropyl-1,2,3-oxathiazolidine 2,2-dioxide (5.83 g, 94% yield) as an orange-brown oil.
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14].[CH3:15]O>CNC>[CH3:3][C:4]1[CH:9]=[C:8]([CH2:1][O:2][CH3:15])[CH:7]=[C:6]([C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]=1[OH:14]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: C=O
Reactant: CO
Agent: CNC
Product: COCc1cc(C)c(O)c(C(C)(C)C)c1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
In a 1 liter stainless steel autoclave was placed 440 ml methanol, 19.6 g (0.65 mole) paraformaldehyde, 5.3 g (0.048 mole) 40 percent aqueous dimethylamine catalyst and 82.4 g (0.5 mole) 2-methyl-6-tert-butylphenol. The autoclave was sealed and heated while stirring to 130° C. Stirring was continued at 130° C. for 3 hours 10 minutes. Analysis by gas chromatograph (GC) showed the reaction forming 2-methyl-6-tert-butyl-4-methoxymethylphenol to be 95 percent complete. The mixture was transferred to a distillation flask under nitrogen and the excess methanol was distilled out up to a flask temperature of 100° C. The residue was cooled and dissolved in 290 g methylene chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([N:23]([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:27])([CH3:26])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:25][N:23]([CH3:24])[C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:27])([CH3:26])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N(C)C)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1cc(F)cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 34.1 %

Procedure:
A mixture of 2-(3-dimethylamino-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.11 g, 0.3 mmol), lithium hydroxide hydrate (0.12 g, 3.0 mmol), water (2 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-dimethylamino-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (35 mg, 30%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C20H23FN2O2 (M+H)+: 343.2, observed: 343.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][NH2:27])[CH3:25]>>[CH2:24]([O:26][N:27]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:23])=[CH:16][CH:17]=1)[CH3:25]
Reactant: CN(CCCCCOc1ccc(C=O)cc1)c1ccc(Cl)nn1
Reactant: CCON
Product: CCON=Cc1ccc(OCCCCCN(C)c2ccc(Cl)nn2)cc1

Procedure:
Reaction of 4-{N-(6-Chloro-3-pyridazinyl)-N-methyl-5-aminopentan-1-oxy}benzaldehyde with ethoxyamine following similar conditions to those in Example 1 gave 4-{N-(6-Chloro-3-pyridazinyl)-N-methyl-5-aminopentan-1-oxy}benzaldehyde O-ethyloxime (Compound 161) as a colourless oil. The nmr and mass spectral data are given below in Table 11.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10].[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[CH2:31][OH:32]>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([O:32][CH2:31][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: OCc1ncccn1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ncccn2)c(-c2ccc(F)cc2)n1

Procedure:
In analogy to example 55, however by starting from 5-bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide and pyrimidin-2-yl-methanol, the title compound was obtained as off-white solid. MS (ISP) (M+H+)=424.2.