Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:5]([CH2:24][CH3:25])[CH:4]=1)=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29]>>[CH2:24]([C:5]1[CH:4]=[C:3]([CH:1]=[C:27]([C:26]#[N:30])[C:28]#[N:29])[CH:8]=[CH:7][C:6]=1[N:9]=[C:10]1[S:14][CH2:13][C:12]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[N:11]1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:25]
Reactant: N#CCC#N
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Product: CCc1cc(C=C(C#N)C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method D11a to give 2-(4-formyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with malononitrile according to Method D12c according to afford 2-(2-ethyl-4-(2,2-dicyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Reaction time: 0.92 h
Yield: 104.5 %

Procedure:
To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (11.98 g, 58.4 mmol, 1 equiv) in THF (80 mL) at 23° C. was added a saturated solution of sodium bicarbonate (200 mL) followed by benzyl chloroformate (9.19 mL, 64.2 mmol, 1.1 equiv). The reaction was stirred for 55 min then partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, washed with saturated brine solution (200 mL), dried (MgSO4), filtered and concentrated to give 20.4 g of tan solid. This material was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[NH:9]1[CH2:12][CH2:11][CH2:10]1>>[Br:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1CNC1
Reactant: Brc1cccc(Br)c1
Product: Brc1cccc(N2CCC2)c1

Procedure:
The title compound was prepared from 1,3-dibromobenzene and azetidine using a similar procedure to that described for D43. LCMS (A): m/z (M+H)+ 212/214, C9H10BrN requires 211/213 (acidic).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:10]1([S:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:17][S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CSc1ccccc1)c1ccccc1O
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Oc1ccccc1C(=CSc1ccccc1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.08 g of imidazole and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. The resultant mixture was stirred for 30 minutes, followed by an addition of 2.10 g of 2-phenylthio-2'-hydroxyacetophenone. The thus-obtained mixture was stirred at room temperature for 2 hours. Ice water was then added to the reaction mixture, followed by its extraction with methylene chloride. The methylene chloride extract was then subjected to a post treatment in the same manner as in Example 10. The reaction product was separated by column chromatography, thereby obtaining 0.2 g of Isomer A (Compound 61) and 1.0 g of Isomer B (Compound 62) of 1-(2-hydroxyphenyl)-1-imidazolyl-2-phenylthioethylene as colorless crystals respectively.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[F:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:19]O>>[F:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9]([O:11][CH3:19])=[O:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (16 mL, 0.22 mol) was added dropwise to cooled (0° C.) methanol (250 mL). After the addition the resulting anhydrous methanolic HCl solution was poured into a flask containing 2-fluoro-5-nitrobenzoic acid (13.77 g, 74.39 mmol). The mixture so obtained was stirred overnight at rt. The reaction mixture was concentrated and the residue collected was purified by flash chromatography using a gradient [silica, 5-30% (700 mL), then 30-50% (1 L)], giving methyl 2-fluoro-5-nitrobenzoate.
Reaction SMILES: [S:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)[C:2]#N.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].CI.CCCCCC>C(O)C.O>[CH3:2][S:1][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: N#CSc1ccc(N)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: CI
Solvent: CCCCCC
Product: CSc1ccc(N)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 4-thiocyano-2-trifluoromethylaniline (2.1 g., 0.01 mole) in ethanol (25 ml) is added to a stirred solution of sodium sulfide nonahydrate (2.4 g., 0.01 mole) in water (5 ml) and the mixture is warmed (50° C.) for 40 minutes. Methyl iodide (1.55 g., 0.011 mole) is added to the warm reaction all at once, and stirring is continued for two hours. Thin layer chromatography on silica gel with 50 percent hexane-50 percent methylene chloride diluent alongside an authentic sample shows that all of the thiocyano compound is reacted to produce the desired product.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[CH3:58][C:59]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=1[S:66](Cl)(=[O:68])=[O:67]>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:66]([C:60]3[CH:61]=[C:62]([F:65])[CH:63]=[CH:64][C:59]=3[CH3:58])(=[O:67])=[O:68])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F
Yield: 46 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (0.082 g, 0.239 mmol) and 2-methyl 5-fluorobenzenesulfonyl chloride (0.055 g, 0.263 mmol) the title compound was obtained (57 mg, 0.11 mmol, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 7.91 (d, J=5.3 Hz, 1H), 7.44 (dd, J=8.8, 2.6 Hz, 1H), 7.29-7.42 (m, 3H) 7.16-7.29 (m, 2H), 6.71 (s, 2H), 5.73 (d, J=5.1 Hz, 1H), 2.49 (s, 3H), 1.35 (s, 9H). MS (ES+): 516 [M+H]+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(O)CO>[Cu]I.CC(O)C>[CH2:9]([NH:16][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: O=C(O)c1ccccc1NCc1ccccc1
Temperature: 80 °C
Yield: 70.8 %

Procedure:
Copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-iodobenzoic acid (248 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL) were used and heated at 80° C. for 18 hours. The above workup procedure was followed and gave 2-(N-benzyl)aminobenzoic acid (161 mg, 71% isolated yield) as a light yellow solid.
Reaction SMILES: C(S)C.C[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1
Reactant: COc1ccc(CC(CC(=O)O)CC(=O)O)cc1
Solvent: CCS
Solvent: CN(C)C=O
Product: O=C(O)CC(CC(=O)O)Cc1ccc(O)cc1
Temperature: 165 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a stirred suspension of 57% sodium hydride-paraffin (1.4 g) in dry dimethylformamide (30 ml) is added dropwise a solution of ethanethiol (4.0 ml) in dry dimethylformamide (10 ml). After 15 minutes, a solution of 3-[(4-methoxyphenyl)methyl]glutaric acid (800 mg) in dry dimethylformamide (20 ml) is added. The resulting slurry is heated in a bath at 165° C. for 20 hours and evaporated in vacuo. The residue is acidified with 20% hydrochloric acid, extracted with ether and the extracts are discarded. The aqueous solution is saturated with salt and extracted with ethyl acetate. The extracts are combined, washed once with brine, dried, evaporated and the residue crystallized from a mixture of ethyl acetate-chloroform-hexane to give 600 mg of 3-[(4-hydroxyphenyl)methyl]glutaric acid, melting point 117°-119° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:12][C:13]1[CH2:17][CH2:16][C:15](=O)[CH:14]=1)C.Cl>CCOCC>[CH2:1]([C:15]1[CH2:16][CH2:17][C:13](=[O:12])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC1=CC(=O)CC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O=C1C=C(Cc2ccccc2)CC1
Temperature: -30 °C
Yield: 75.6 %

Procedure:
To a −78° C. solution of benzyl magnesium chloride (14.3 mL, 28.5 mmol, 1.2 eq, 2 M solution in THF) in ether (50 mL) was slowly added 3-ethoxycyclopent-2-enone (2.84 mL, 23.8 mmol, 1 eq.). The reaction mixture was warmed up to −30° C. over 1 hour. At this point, a 1 M solution of HCl was added to the reaction mixture until the pH was adjusted to 1 as indicated by litmus paper. The solution was warmed up to room temperature and the layers were separated. The aqueous phase was extracted with 40 mL of Et2O (3×) and the combined organic layers were washed with 100 mL of brine (1×), dried over anhydrous MgSO4 and concentrated in vacuo. The residual oil was purified by flash chromatography (25% EtOAc/hexanes) to give (3.1 g, 76% yield) of the title compound as a colorless oil.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].[CH3:18]O>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:18])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: CO
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
Thionyl chloride (24 g, 201.68 mmol, 1.01 equiv) was added dropwise with stirring at 0° C. to a solution of 4-fluoro-3-nitrobenzoic acid (37 g, 200.00 mmol, 1.00 equiv) in MeOH (400 mL) and allowed to react, with stifling, for 3 hrs under reflux. The resulting mixture was concentrated under vacuum, diluted with 500 mL of EA, and washed with 3×200 mL of saturated NaHCO3 and 1×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum affording 40 g (crude) of methyl 4-fluoro-3-nitrobenzoate as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[CH:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl>C(Cl)Cl.CO>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:12][C:9]3[CH:10]=[CH:11][C:5]4[O:4][C:3]([N:2]([CH3:1])[CH2:13][CH:14]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]5)=[N:7][C:6]=4[CH:8]=3)=[O:31])=[CH:33][CH:34]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(C5CCCCC5)cc4)ccc3o2)C1
Reaction time: 0.17 h
Yield: 40 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.150 g, 0.576 mmol), 4-cyclohexyl-benzoic acid (0.177 g, 0.864 mmol), HATU (0.219 g, 0.576 mmol), polystyrene-bound diisopropylamine (1.44 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (20 mL). Shake the mixture overnight at room temperature. Add HATU (0.219 g, 0.576 mmol) and shake for 21 h at room temperature. Dilute with 1:1 CH2Cl2/MeOH, wash with 10M NaOH (equal volume), dry over Na2SO4, filter, and concentrate in vacuo. Subject the mixture to silica gel flash column chromatography (2×12 g columns, 5% 2M NH3 in MeOH/CH2Cl2, then ramping to 10% after 10 min) to yield the desired product as a colorless oil (0.103 g, 40%). Subject the product to chiral preparative chromatography [Chiralpak AD-H column, (8×32 cm), eluting with 70/30 3 Å ethanol/ACN w/0.2% dimethylethylamine; Flow rate=350 mL/min] to yield isomer 1 (0.039 g). mass spectrum (m/e): 447.3 (M+1). 1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.80-7.76 (m, 2H), 7.48 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.6, 1.8 Hz, 1H), 7.31-7.27 (m, 2H), 7.20 (d, J=8.4 Hz, 1H), 3.61-3.46 (m, 2H), 3.19 (s, 3H), 2.77-2.51 (m, 6H), 2.42-2.37 (m, 1H), 2.37 (s, 3H), 2.07-1.97 (m, 1H), 1.91-1.80 (m, 4H), 1.76 (d, J=12.8 Hz, 1H), 1.61-1.52 (m, 1H), 1.48-1.22 (m, 4H).
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:10][C:2]1[O:18][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: NC(=O)c1ccccc1
Reactant: COC(=O)CC(=O)C(C)Br
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C

Procedure:
reacting methyl 4-bromo-3-oxovalerate with benzamide to give methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate, or reacting ethyl 4-bromo-3-oxovalerate with benzamide to give ethyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate,
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH3:10][C:2]1[O:18][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: NC(=O)c1ccccc1
Reactant: COC(=O)CC(=O)C(C)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A 500-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a Claisen head with a condenser and a receiver connected to a cold trap and a vacuum controller was charged with 52.26 g of crude methyl 4-bromo-3-oxovalerate (ca. 0.250 mol) and 46.5 g of benzamide. A vacuum of 400 mbar was applied and the suspension was stirred at 90° C. for 18 h. After ca. 3 h the suspension had become a clear orange oil. After cooling to rt 300 ml of methanol and 1.0 g of p-toluenesulfonic acid monohydrate were added and the brown solution was stirred at reflux (ca. 73° C.) for 1 h. After this time 50 ml of methanol were distilled off, 50 ml of methanol were added and the mixture was heated at reflux for additional 30 min. After cooling and rotary evaporation (50° C., 8 mbar, 30 min), the residue was treated under argon with 150 ml of toluene and 125 ml of sat. aqueous sodium bicarbonate solution. The resulting suspension was stirred in an ice bath for 1 h, the precipitated benzamide was filtered off with suction and the filter cake was washed twice with a small amount of ice-cold toluene and water. The combined aqueous phases were extracted in a separatory funnel with 100 ml of toluene. Thereafter the combined organic phases were washed twice with 30 ml, a total of 60 ml of deionized water, dried (Na2SO4) and rotary evaporated (50° C., 8 mbar, 1 h) to give 49.22 g of crude Methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (theor. amount 57.81 g) as a yellow oil, which was used without purification in the next step.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
In a 1-L three-neck flask, o-phenylenediamine (56.13 g) was added to pyridine (350 ml) and the resultant solution was stirred with a stirrer bar to dissolve the compound. The solution was cooled in an ice-water bath, so that the temperature inside the reaction mixture became 2-3° C. 4-Chlorophenylsulfonyl chloride (73.04 g) was dissolved in pyridine (100 ml) and the resultant solution was added dropwise to the aforementioned mixture by using dropping funnel. The reaction temperature was maintained at 10° C. or lower and the dropping step required 70 minutes. The reaction mixture exhibited deep-purplish-red color. Subsequently, the mixture was stirred at 10° C. or lower for 15 minutes. The flask was removed from the ice-water bath and returned to room temperature. The mixture was further stirred for one hour. The solvent, pyridine, was removed with an aspirator under reduced pressure at 50° C. and the residue was diluted in ethyl acetate (1 L). The resultant solution was transferred to a 2-L separating funnel and water (0.5 L) and an adequate volume of a 2N hydrochloride solution were added thereto. The volume of the 2N hydrochloride solution to be added was regulated so that the pH of the washing solution became 2-3. The washing solution was extracted with ethyl acetate (0.3 L×2). The thus-obtained ethyl acetate layer was washed with saturated brine (0.3 L×3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and red crystals were precipitated. Ethyl acetate (0.3 L) was added to the thus-obtained crystals to dissolve the crystals. Subsequently, the crystals were re-crystallized from the mixture of solvents (hexane:ethyl acetate=10:1). The thus-produced crystals were collected through suction-filtration, washed with the same solvent mixture, and air-dried, to thereby yield pale-yellow crystals (79.28 g). The mother liquid for re-crystallization and the washing solution were combined. Subsequently, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), and the mixture of solvents (100 ml) (hexane:ethyl acetate=10:1) was added thereto, followed by re-crystallization. The thus-obtained crystals were subjected to suction-filtration, washed, and air-dried, to thereby produce pale-yellow crystals (6.41 g). Through the second re-crystallization, the target product (85.69 g) was obtained.
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][N:34]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][CH:13]=3)[C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Yield: 92 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(trifluoromethyl)benzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 92% yield: mp 126-127° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 4.51 (s, 2H), 4.17 (q, J=6.9 Hz, 2H), 4.00 (t, J=8.1 Hz, 2H), 3.47 (t, J=8.1 Hz, 2H), 2.49 (s, 3H), 1.23 (t, J=6.9 Hz, 3H); MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [I:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>CO>[OH:13][CH2:12][C:11]1[C:2]([I:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1cc2ccccc2nc1I
Solvent: CO
Product: OCc1cc2ccccc2nc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
To a stirred solution of 2-iodo-3-quinolinecarboxaldehyde (595 mg, 2 10 mmol) in 40 mL of CH3OH at 0° C. was added NaBH (86 mg, 2.31 mmol), and the mixture was stirred at 0° C. for 30 min. After concentrating the mixture to approximately one-half of its original volume, water (30 mL) was added and the mixture was allowed to stand at 5° C. overnight. The solids were filtered and the crude product (570 mg, 95%) was recrystallized from methanol to give 3-hydroxymethyl-2-iodoquinoline (505 mg, 84%) as colorless needles: mp 189°-190° C. 1H NMR (300 MHz, CDCl3)δ8.19 (s, 1H), 7.99 (d, 1H, J =9 Hz), 7.87 (d, 1H, J =9 Hz), 7.68 (m, 1H), 7.58 (t, 1H, J =9 Hz), 5.45 (t, 1H, J =6 Hz), 4.66 (d, 2H, J =6 Hz); IR (nujol) 3350, 1580, 1320, 1125, 1060, 995, 755, 720, cm-1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].O>N1C=CC=CC=1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[CH3:17])(=[O:4])=[O:3]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (2.98 ml, 38.6 mmol) was added to an ice-cold solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (Synth. Commun. 1993; 23(17); 2443) (4.5 g, 25.7 mmol) in pyridine (40 ml), and the reaction stirred for 2 hours. The solution was poured into water (150 ml), and extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with 10% aqueous citric acid solution, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (34:66 to 40:60) to give the title compound, 1.0 g.