Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]([NH2:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C(O)C>[CH2:22]([NH:25][S:18]([C:4]1[CH:5]=[C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])[CH:7]=[CH:8][C:3]=1[Cl:2])(=[O:20])=[O:19])[CH:23]=[CH2:24]
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: C=CCN
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCNS(=O)(=O)c1cc(C2(O)CSC(=NC)N2C)ccc1Cl

Procedure:
8.7 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of allyl amine and 4 g of triethyl amine in 50 ml of ethanol and worked up. The water was decanted and the amorphous end product was crystallized under diethyl ether. Colorless solid body, melting point: 146° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][C@H:6]1[OH:21].[H][H].C(OCC)C>CO.[Pd]>[CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@H:6]1[OH:21]
Reactant: Cc1cccc(O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: Cc1cccc(O[C@H]2CCNC[C@H]2O)c1C
Yield: 67.8 %

Procedure:
A solution of cis-benzyl 4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate (5.0 g, 14.0 mmol) in methanol (60 ml) was added to 5% palladium on charcoal (500 mg) under an atmosphere of nitrogen. The vessel was placed under an atmosphere of hydrogen and stirred vigorously until hydrogen uptake ceased. The resulting suspension was filtered over a short pad of celite (pre-washed with methanol) and the pad washed with a further portion of methanol (150 ml). Concentration of the methanolic solution in vacuo gave a yellow oil. Dilution with diethyl ether (150 ml) yielded cis-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine as a white solid (2.1 g, 67%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:13].[C:14]1(=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[O:15]1.CC1C=CC=CC=1>O>[O:15]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:1]1[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)N1CC[C@@H](N)[C@H](O)C1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC[C@@H](N2C(=O)c3ccccc3C2=O)[C@H](O)C1

Procedure:
A mixture of 4.7 parts of ethyl trans-4-amino-3-hydroxy-1-piperidinecarboxylate, 3.7 parts of 1,3-dihydroisobenzofuran-1,3-dione and 45 parts of methylbenzene was stirred and refluxed for 2 hours using a water-separator. The reaction mixture was decanted from some insoluble tar. The methylbenzene-phase was evaporated in vacuo in a boiling water-bath. The residue was boiled in 2,2'-oxybispropane. After cooling, the solvent was decanted. The remaining oil solidified on scratching in 2,2'-oxybispropane. The product was filtered off and dissolved in dichloromethane. The solution was washed successively with a dilute hydrochloric acid solution, water, a dilute sodium hydroxide solution and again water. The organic phase was dried, filtered and evaporated in vacuo. The residue solidified on scratching in 2,2'-oxybispropane. The product was filtered off and crystallized from 2-propanol, yielding 2.12 parts of ethyl trans-4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-hydroxy-1-piperidinecarboxylate; mp. 128.4° C. (intermediate 57).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][S:36]([CH3:35])(=[O:38])=[O:37])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanamine (100 mg, 0.257 mmol) was dissolved in dichloromethane (2.6 mL) and pyridine (0.208 mL, 2.57 mmol) before methanesulfonyl chloride (30 μl, 0.385 mmol) was added and stirred at ambient temperature for 3 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with 1 N HCl (aqueous), washed with 1 N HCl (aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after purification via preparatory LC. MS (ESI) m/z: Calculated: 467.1; Observed: 468.1 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[CH:5]=[CH:4][N:3]=1.[Br:10]Br>>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([Br:10])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1nccc(F)c1O
Product: Nc1ncc(Br)c(F)c1O

Procedure:
The 2-amino-4-fluoro-3-pyridinol from Example 2 and bromine in a molar ratio of 1:1 are heated in the vapor phase at 300° according to the procedure of McElvain and Goese [J. Am. Chem. Soc., 65, 2227 (1943)] to give 2-amino-5-bromo-4-fluoro-3-pyridinol. The latter with an equivalent amount of cesium fluoride by the procedure of Example 2gives 2-amino-4,5-difluoro-3-pyridinol.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:44]([NH:43][C:41](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[F:34])=[S:45])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccccc1F
Agent: O=C(N=C=S)c1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4F)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
2-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1
Reactant: COc1cc(C=O)ccc1-c1cccc(C)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2)ccc1-c1cccc(C)c1
Temperature: -20 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
The aldehyde 5 were dissolved in dry THF and cooled to −20° C. Phenylmagnesium bromide (1.2 eq, 1.651 mM) was then added to the reaction and the reaction was stirred for an additional 2 hrs. After the completion of the reaction as determined by TLC, the reaction mixture was quenched with 0.1 N HCl, followed by washes with saturated sodium bicarbonate solution and brine. The organic layer was then evaporated and the product was purified by flash chromatography using 20% EtOAc/Hexanes as the solvent system to obtain a white solid. Yield=78.0% (Rf=0.48; 20% EtOAc/Hexanes) 1H NMR, 500 MHz Varian, CDCl3, δ 10.01 (s, 1H), 7.53 (d, J=15.00 Hz, 1H), 7.51 (d, J=15.00 Hz, 1H), 7.49 (d, J=10.00 Hz, 1H), 7.34 (s, 3H), 7.21 (d, J=7.0, 1H), 3.89 (s, 3H), 2.41 s, 3H), MS: m/z (ESI, pos.)=327.8 ([M+23])
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:7]([O:25][CH3:26])=[C:8]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:9]([F:13])=[C:10]([Cl:12])[CH:11]=1)[CH3:5])=[N+]=[N-].CP(C)C>C1COCC1.O>[NH2:1][CH:4]([C:6]1[C:7]([O:25][CH3:26])=[C:8]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:15]2)[C:9]([F:13])=[C:10]([Cl:12])[CH:11]=1)[CH3:5]
Reactant: COc1c(C(C)N=[N+]=[N-])cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(C)N)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 3-[3-(1-azidoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetidine-1-carboxylate (0.084 g, 0.22 mmol) in THF (1 mL)/water (0.2 mL) was added 1.0 M trimethylphosphine in THF (0.33 mL, 0.33 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give the desired product to be used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CC(C)=O.C(OCC)C>[C:17]([O:20][CH2:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10])(=[O:19])[CH3:18]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)OCCOc1ccc(C=O)cc1C
Yield: 97.5 %

Procedure:
A mixture of 4-hydroxy-3-methyl-benzaldehyde (7.0 g, 51.4 mmol), K2CO3 (21.32 g, 154.2 mmol) and 2-bromoethyl acetate (25.8 g, 154.2 mmol) in acetone (250 mL) is refluxed for 18 h before it is diluted with diethyl ether (300 mL) and washed with water (3×250 mL). The washings are extracted with diethyl ether (200 mL). The combined organic extracts are dried over MgSO4 and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to afford the title compound (11.14 g) as colourless solid. 1H NMR (CDCl3): δ 9.85 (s, 1H), 7.72-7.67 (m, 2H), 6.92-6.88 (m, 1H), 4.51-4.46 (m, 2H), 4.29-4.25 (m, 2H), 2.27 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:39])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[C:10]([I:39])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2snc(-c3ccc(F)cc3)c2c1O
Reactant: Cc1cc(C)c([IH+])c(C)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)c1nc(I)c2snc(-c3ccc(F)cc3)c2c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (400 mg, 1.25 mmol) in CH2Cl2 (12.5 mL) was added bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.29 g, 2.51 mmol). The reaction mixture was allowed to stir at r.t. for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the title product (382 mg) as a yellow solid: MS (m/z) 442.9 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[NH:12]1>>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([N:12]2[C@H:13]([CH3:17])[CH2:14][CH2:15][CH2:16][C@@H:11]2[CH3:10])[N:3]=[CH:4][N:5]=1
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: C[C@@H]1CCC[C@H](C)N1
Product: C[C@@H]1CCC[C@H](C)N1c1ncnc(Cl)c1F
Temperature: 70 °C
Reaction time: 11 h
Yield: 57.5 %

Procedure:
0.25 g of 4,6-dichloro-5-fluoropyrimidine and 0.34 g of cis-2,6-dimethylpiperidine were mixed and stirred for 11 hours at 70° C. The reaction mixture was subjected to silica gel column chromatography to obtain 0.21 g of 4-chloro-6-(cis-2,6-dimethylpiperidino)-5-fluoropyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)([CH3:11])[C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[CH2:29]([NH2:32])[CH:30]=[CH2:31]>C(Cl)Cl>[CH2:29]([NH:32][C:4]1[C:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:30]=[CH2:31]
Reactant: CC1(c2ccc(F)cc2)CCc2c(Cl)nc(Cl)nc21
Reactant: C=CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCNc1nc(Cl)nc2c1CCC2(C)c1ccc(F)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation U, 1.00 g, 3.37 mmol) in DCM (13.46 mL) was added DIPEA (1.176 ml, 6.73 mmol), then allylamine (0.303 ml, 4.04 mmol). The reaction solution was allowed to stir at rt. The reaction was concentrated in vacuo. The residue was applied to silica gel and eluted with a 0 to 50% EtOAc/Hexane gradient to afford N-allyl-2-chloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (896.2 mg, 2.82 mmol, 84% yield) as a white solid. LC-MS (M+H)+=316.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.18-7.23 (2H, m), 6.91-6.98 (2H, m), 5.90-6.00 (1H, m), 5.26 (1H, dd, J=17.2, 1.4 Hz), 5.20 (1H, dd, J=10.1, 1.2 Hz), 4.62 (1H, br. s), 4.17 (1H, td, J=5.7, 1.7 Hz), 2.56-2.62 (2H, m), 2.43-2.50 (1H, m), 2.19-2.28 (1H, m), 1.63 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Cl[CH2:10][CH:11]=O.C(=O)([O-])O.[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[CH:11][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1ccn2ccnc2c1
Yield: 75 %

Procedure:
A stirred suspension of 4-chloropyridin-2-ylamine (6.20 g, 48.2 mmol), chloroacetaldehyde (11.4 g of a 50 wt % solution in water, 73 mmol) and sodium hydrogencarbonate (8.09 g, 96.4 mmol) in ethanol (70 ml) was heated under reflux for 6 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate and concentrated in vacuo to give an orange oil. This oil was purified by silica gel chromatography eluting with 50% ethyl acetate in isohexane to afford 7-chloroimidazo[1,2-α]pyridine (5.60 g, 75%) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δH 6.78 (1H, d, J 7), 7.56 (1H, s), 7.63 (2H, s), 8.05 (1H, d, J 7).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:13][C:14](=[O:39])[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23](=O)[NH:24][CH2:25][C:26](=O)[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(=O)C>[CH2:6]([O:13][C:14](=[O:39])[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[N:5]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(NCC1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1)OCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C(NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1)OCc1ccccc1

Procedure:
Ammonium acetate (26 g, 0.34 mol) was added to a solution of {4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamic acid benzyl ester (5.4 g, 0.0113 mol) in acetic acid. The resulting homogeneous mixture was refluxed overnight and then concentrated under reduced pressure. The residue was partitioned between 10% NaOH and EtOAc (1:1) and the EtOAc layer was washed with 10% NaOH (3×) and brine. The EtOAc was dried (Na2SO4) and concentrated under reduced pressure to give {4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-carbamic acid benzyl ester. 1H NMR (CDCl3): δ 1.02–1.18 (m, 2H), 1.46–1.62 (m, 3H), 1.86–1.96 (m, 2H), 2.12–2.21 (m, 2H), 2.74 (m, 1H), 3.10 (t, J=6 Hz, 2H), 4.91 (t, 1H, N—H), 5.10 (s, 2H), 7.22 (s, 1H), 7.32–7.37 (m, 5H), 7.45 (d, J=4.9 hz, 2H), 7.87 (m, 1H), 7.95 (s, 1H). MS 458 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].C(=O)(O)[O-].[Na+].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[N:6][C:5]=1[NH2:10]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cccnc1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])cnc1N
Temperature: 0 °C
Reaction time: 19 h
Yield: 35 %

Procedure:
2-Amino-nicotinic acid methyl ester (1.00 g, 6.57 mmol) described in Preparation Example A-2 was dissolved at 0° C. in a mixed solution of nitric acid (0.7 mL) and sulfuric acid (2.6 mL), which was stirred at 0° C. for 40 minute and at room temperature for 19 hours, then, further stirred at 70° C. for 4 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution at 0° C., which was extracted with ethyl acetate and tetrahydrofuran, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. Methanol was added to the residue, the precipitated solid was filtered to obtain the title compound (459 mg, 2.33 mmol, 35%) as a white solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([NH:35]N)[C:29]=2[O:28][CH2:27][CH2:26]1>>[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([N:35]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[C:29]=2[O:28][CH2:27][CH2:26]1
Reactant: NNc1cccc2c1OCCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4c3OCCO4)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (2,3-dihydro-benzo[1,4]dioxin-5-yl)-hydrazine according to the method described for example 43. MS: M=451.2 (M+H)+
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([OH:20])=O)[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([NH:32][CH2:31][CH2:29][OH:30])=[O:20])[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: NCCO
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)NCCO)C1(C)C

Procedure:
The product from Example 205 and ethanolamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.14 (s, 3H), 1.23 (s, 3H), 1.26-1.42 (m, 3H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.69-1.82 (m, 1H), 2.25-2.47 (m, 2H), 2.61-2.67 (m, 2H), 2.96-3.02 (m, 1H), 3.09-3.15 (m, 2H), 3.33-3.39 (m, 2H), 4.61 (t, J=5.3 HZ, 1H), 7.20 (t, J=5.5 Hz, 1H), 8.50 (s, 1H). (ESI+) m/z 438 (M+H)+. Anal. calcd. for C23H39N3O3S: C, 63.12; H, 8.98; N, 9.60. Found: C, 62.89; H, 8.84; N, 9.72.
Reaction SMILES: [C:1]1([N:7]=[C:8]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:10]>>[C:1]1([NH:7][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: S=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1

Procedure:
Isothiocyanates may be converted to ureas and thus phenyl isothiocyanate, on oxidation with a telluroxide in the presence of water (e.g. of formula (I) as hereinbefore defined), gives 1,3-diphenylurea.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>CC#N>[CH3:14][O:13][C:5]1[C:6]([CH3:12])=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)[N:11]=[CH:10]2
Reactant: COc1c(C)ccc2cnc(Cl)nc12
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-8-methoxy-7-methylquinazoline (20.4 g, 0.098 mol) in CH3CN (800 mL) were added trans-4-amino-cyclohexanol (22.5 g, 0.195 mol) and DBU (29.7 g, 0.195 mol) in one portion. The reaction mixture was refluxed with stirring overnight. TLC (ethyl acetate/petroleum ether=1:1) indicated the reaction was complete. The solvent was removed in vacuo. The residue was taken up with CHCl3 (550 mL), the solution was washed with water (150 mL×2). The aqueous layer was re-extracted with CHCl3 (150 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product. The crude product was re-crystallized from EtOH (130 mL)/water (200 mL) to give the title compound (17 g, 60.5%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:18]([OH:22])[CH:19]([OH:21])[CH3:20]>CCCCC>[OH:21][CH:19]([CH3:20])[CH2:18][O:22][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: CC(O)CO
Solvent: CCCCC
Product: CC(O)COc1c2ccccc2c(C=O)c2ccccc12
Yield: 29.5 %

Procedure:
Using the procedure outlined in Example 2A, 10-chloroanthracene-9-carbaldehyde (Aldrich) and 1,2-propyleneglycol (Aldrich) gave a 29.5% yield of 10-[2-(hydroxy)propoxy]anthracene-9-carbaldehyde, mp 84°-86°, (C,H), (pentane).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b (with gradient: 5% B→95% B over 1 min): tR=0.79 min; [M+H]+=425.14.