Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[Mg]Br>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:11]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=1)[OH:12]
Reactant: Br[Mg]c1ccco1
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Product: OC(c1ccc(-c2ccccc2)nc1)c1ccco1

Procedure:
Synthesized using compound 43b (650 mg, 3.75 mmol) and furan-2-ylmagnesium bromide (1.85 g, 10.8 mmol, 2 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (6:1) as eluent. Yellow solid. Yield: 631 mg, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.62 (br. s., 1H), 5.86 (s, 1H), 6.17 (d, J=3.4 Hz, 1H), 6.33 (dd, J=3.0, 1.8 Hz, 1H), 7.33-7.51 (m, 4H), 7.69 (d, J=7.9 Hz, 1H), 7.83 (dd, J=8.2, 1.8 Hz, 1H), 7.88-7.99 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=66.7, 106.7, 109.3, 119.4, 126.0, 127.7, 128.0, 134.0, 134.3, 137.9, 141.8, 147.1, 154.1, 156.1; (ESI): m/z=251.87 [M+H]+.
Reaction SMILES: [NH:1]([C:8]1[N:9]=[N:10][NH:11][C:12]=1[C:13]([O:15]CC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+]>[NH:1]([C:8]1[N:9]=[N:10][NH:11][C:12]=1[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]nnc1Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1[nH]nnc1Nc1ccccc1

Procedure:
Hydrolysis of ethyl 4-anilino-1,2,3-triazole-5-carboxylate (9.29 g; 0.04 mole) with 1.25 N sodium hydroxide (200 ml) at 90° C. for 18 hrs. gave the free acid in quantitative yield. Recrystallisation from water containing a minimum of ethanol gave material of mp 149.5-150.5° C. (dec) (lit. mp. 153° C., O. Dimroth Annalen 364 183 [1909]), (Found; C, 52.88; H, 4.14; N, 27.36; C9H8N4O2 requires; C, 52.94; H, 3.95; N, 27.44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:37])([F:36])[C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][C:33](=N)[NH2:34])[CH:28]=[CH:29][CH:30]=1>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:34][C:33]([CH2:32][CH2:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:37])[F:36])[CH:26]=4)=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: N=C(N)CCc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1n(Cc2nnc(CCc3cccc(C(F)(F)F)c3)[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
50 mg (0.16 mmol) of the compound from Example 21A were taken up in 1 ml of DMF, 62 mg (0.24 mmol) of 3-[3-(trifluoromethyl)phenyl]propaneimidamide hydrochloride were added and the mixture was stirred in a microwave oven at 180° C. for 1 h. After cooling, the reaction mixture was diluted with methanol and the solution was directly separated by preparative HPLC [Method 19]. This gave 11 mg (14% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].FC1C=CC(CO)=CC=1.FC1C=C2[C:36]([C:37](=[O:43])[NH:38]C=N2)=CC=1.Cl>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:18])[N:13]([CH2:36][C:37]([NH2:38])=[O:43])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccc(F)cc3)ccc12
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: Cl
Agent: OCc1ccc(F)cc1
Agent: [H-]
Solvent: CN(C)C=O
Product: NC(=O)Cn1cnc2cc(OCc3ccc(F)cc3)ccc2c1=O
Temperature: 140 °C
Yield: 66 %

Procedure:
7-(4-Fluoro-benzyloxy)-3H-quinazolin-4-one: A mixture of sodium hydride (55%, 3.2 g, 73 mmol), 4-fluorobenzyl alcohol (9.2 g, 73 mmol) and 7-fluoro-3H-quinazolin-4-one (3.0 g, 18 mmol) in DMF (75 mL) was heated at 140° C. for 2 h. The resulting suspension was cooled to rt and the mixture acidified to pH 3 with HCl (conc.). The resulting precipitate was then filtered off, washed with water and diethylether. Partial purification by chromatography on silica gel eluting with ethyl acetate:hexane (2:1) afforded the title compound (3.2 g, 66%) as an off-white solid. MS: m/e=271.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C[Si]([C:29]#[CH:30])(C)C.C(N(CC)CC)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1)#[CH:30]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Nc2nc(-c3ccc(Br)cc3)nc3ccccc23)[nH]n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc(-c2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a mixture of [2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (III-34) (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol) in DMF (2 mL) was added CuI (1.1 mg, 1:50 mol %), Pd(PPh3)2Cl2 (4.2 mg, 1:50 mol %) and triethylamine (121 mg, 0.36 mmol). The resulting mixture was heated at 120° C. overnight and the solvent evaporated. The residue was triturated in ethyl acetate and the resulting precipitate collected by filtration. The collected solid was suspended in THF (3 mL) and TBAF (1M in THF, 1.1 eq) was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated. The residue was purified by flash chromatography (silica gel, gradient of DCM:MeOH) to afford III-48 as a white solid (68 mg, 70%): 1H NMR (DMSO) δ 2.34 (3H, s), 4.36 (1H, s), 6.74 (1H, s), 7.55 (1H, m), 7.65 (2H, d), 7.84 (2H, m), 8.47 (2H, d), 8.65 (1H, d), 10.43 (1H, s), 12.24 (1H, s); MS 326.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Br)[C:9]#[CH:10].[O:12]=[C:13]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[C:22]([O:24][CH3:25])=[O:23].O>CN(C)C=O.C(OCC)(=O)C>[CH3:8][C:9]#[C:10][N:19]1[CH2:20][CH2:21][C@@H:16]([CH2:15][CH2:14][C:13](=[O:12])[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][CH:27]=2)[C@@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18]1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: C#CCBr
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC#CN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Temperature: 45 °C

Procedure:
23.7 cm3 of triethylamine and 6.35 cm3 of propargyl bromide are added at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 14.43 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 350 cm3 of anhydrous dimethylformamide. After heating for 5 hours at a temperature in the region of 45° C., the reaction mixture is cooled to approximately 20° C., poured into 190 cm3 of water and 190 cm3 of ethyl acetate, and then extracted with 3 times 250 cm3 of ethyl acetate. The organic extracts are combined, washed 3 times with 250 cm3 of water, dried over sodium sulfate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; diameter 8 cm; mass 600 g), elution being carried out with ethyl acetate and an ethyl acetate/methanol (95/05 by volume) mixture and 400-cm3 fractions being collected. Fractions 3 to 13 are combined and then concentrated under the above conditions. 17.5 g of methyl (3R,4R)-1-(3-prop-2-ynyl)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]([NH2:17])=[S:16]>>[NH2:17][C:15]1[S:16][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)[N:14]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Product: Nc1nc(-c2cccc(C(F)(F)F)c2)cs1
Yield: 94.1 %

Procedure:
Using 3′-(trifluoromethyl)acetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.C[N:20]1[C:24](=[O:25])[CH2:23][S:22][C:21]1=[S:26].NCCC(O)=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1/[CH:13]=[C:23]1/[C:24](=[O:25])[NH:20][C:21](=[S:26])[S:22]/1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Reactant: CN1C(=O)CSC1=S
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\SC(=S)NC2=O)c1Cl
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a room temperature solution of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde (276 mg, 0.99 mmols) and 3-methylrhodanine (166 mg, 1.13 mmols) in 15 mL of acetic acid is added β-alanine (102 mg, 1.14 mmols). The solution is heated at reflux for 3.5 h. The solution is cooled to room temperature and the resulting precipitate is collected by filtration to provide 258 mg (64%) of (Z)-5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-thioxo-4-thiazolidinone as a bright orange solid; mp=175°-176° C. Calc'd for C18H14Cl2N2OS2:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:13]([F:32])=[CH:12][N:11]=1>>[F:32][C:13]1[C:14]([NH:16][CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[N:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1NC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: Oc1cccc(Nc2ncc(F)c(NC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and N-(2-chloro-5-fluoro-pyrimidinyl)-1,1-di(4-chlorophenyl)methylamine produced 5-fluoro-N2-(3-hydroxyphenyl)-N4-[di-(4-chlorophenyl)methyl]-2,4-pyrimidinediamine. LCMS: ret. time: 25.59 min.; purity: 91%; MS (m/e): 421 (MH+—Cl).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:9]1[C:10]2[NH:14][C:13]([C:15]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([O:57]C)=[O:56])=[CH:51][CH:50]=3)=[C:16]3[N:48]=[C:19]([C:20]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46]C)=[O:45])=[CH:40][CH:39]=4)=[C:21]4[NH:37][C:24](=[C:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.Cl>CO.C1COCC1>[C:44]([C:41]1[CH:42]=[CH:43][C:38]([C:20]2[C:21]3[NH:37][C:24]([C:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:26]4[N:30]=[C:29]([C:9]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:10]5[NH:14][C:13](=[C:15]([C:49]6[CH:50]=[CH:51][C:52]([C:55]([OH:57])=[O:56])=[CH:53][CH:54]=6)[C:16]6[CH:17]=[CH:18][C:19]=2[N:48]=6)[CH:12]=[CH:11]5)[CH:28]=[CH:27]4)=[CH:23][CH:22]=3)=[CH:39][CH:40]=1)([OH:46])=[O:45]
Reactant: CCCCCCc1c2nc(c(CCCCCC)c3ccc([nH]3)c(-c3ccc(C(=O)OC)cc3)c3nc(c(-c4ccc(C(=O)OC)cc4)c4ccc1[nH]4)C=C3)C=C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1c2nc(c(CCCCCC)c3ccc([nH]3)c(-c3ccc(C(=O)O)cc3)c3nc(c(-c4ccc(C(=O)O)cc4)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 48 h

Procedure:
In a typical experiment, a solution of KOH (200 mg, 3.6 mmol) in methanol (1 ml) was added to a stirred solution of 5,10-dihexyl-15,20-bis-(4-methoxycarbonylphenyl)-porphyrin (34 mg, 0.05 mmol) in THF (8 ml) and the reaction mixture was stirred for 2 d. Water (50 ml) and hydrochloric acid were then added until the pH was adjusted to 4-6. The aqueous layer was extracted with dichloromethane (2×100 ml) and the organic layer was separated, washed with water until neutral and dried over sodium sulfate. The solvent was evaporated and the title compound 5,10-bis-(4-carboxyphenyl)-15,20-dihexyl-porphyrin was obtained after recrystallization from dichloromethane/aqueous methanol (26 mg, 79%).
Reaction SMILES: [NH2:1][C:2](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([F:18])[CH:4]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=O)=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38]>>[F:18][C:5]1[CH:4]=[C:3]([C:2]2[N:1]=[C:32]([C:31]3[CH:35]=[CH:36][C:28]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]4[CH3:21])=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:30]=3)[O:20][N:19]=2)[CH:17]=[CH:16][C:6]=1[O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc(OCC(=O)OC(C)(C)C)c(F)c3)no2)cc1C(F)(F)F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 49 (142.14 mg; 0.50 mmol) and Intermediate 15 (172.37 mg; 0.60 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a white solid. LC/MS (Method B): 536.4 (M+H)+. HPLC (Method A) Rt 7.2 min (Purity: 99.4%).
Reaction SMILES: Cl.[NH2:2]O.[C:4](/[N:12]=[C:13](\SC)/[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([C:22]2[C:23](=[O:34])[N:24]([CH3:33])[C:25]3[C:30]([CH:31]=2)=[CH:29][N:28]=[C:27]([CH3:32])[CH:26]=3)[CH:16]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCO>[CH3:33][N:24]1[C:25]2[C:30](=[CH:29][N:28]=[C:27]([CH3:32])[CH:26]=2)[CH:31]=[C:22]([C:17]2[CH:16]=[C:15]([NH:14][C:13]3[N:12]=[C:4]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[O:11][N:2]=3)[CH:20]=[CH:19][C:18]=2[CH3:21])[C:23]1=[O:34]
Reactant: NO
Reactant: CS/C(=N\C(=O)c1ccccc1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4ccccc4)n3)ccc1C)c(=O)n2C
Temperature: 80 °C

Procedure:
Hydroxylamine hydrochloride (35 mg, 0.5 mmol) and EtOH (1 mL) were added to the crude 21 (0.05 mmol). The mixture was heated at 80° C. for 2 h. After filtration, the mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-phenyl-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one A7. 1H NMR (400 MHz, d4-MeOH) δ 9.03 (s, 1H), 8.12 (s, 1H), 8.1 (d, J=1.5 Hz, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7.65 (d, J=6.2 Hz, 1H), 7.59 (d, J=6.3 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.5 (d, J=2.4 Hz, 1H), 7.43 (dd, J=8.3, 2.5 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 2.83 (s, 3H), 2.18 (s, 3H). MS m/z 424.1 (M+1).
Reaction SMILES: CSC.[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:6]=1[CH2:7]O.C(Cl)[Cl:17]>>[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:6]=1[CH2:7][Cl:17]
Reactant: CN(C)c1ccc(Cl)c(CO)c1
Reactant: ClCCl
Solvent: CSC
Product: CN(C)c1ccc(Cl)c(CCl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
23.8 g of N-chlorosuccinimide provided in 600 ml of absolute methylene chloride is cooled to 0° C. and is slowly mixed with 15.6 ml of dimethyl sulfide. Thereafter the suspension thus produced is cooled to -30° C. and carefully mixed with 20 g of 2-chloro-5-dimethylaminobenzyl alcohol. The reaction mixture is then warmed to 0° C. and stirred at this temperature for 3 hours. Thereafter the mixture is diluted with methylene chloride and poured into ice water. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate solution and concentrated in vacuo. The residue is chromatographed with hexane over aluminum oxide (neutral, stage III). A yield of 17.2 g of 2-chloro-5-dimethylaminobenzyl chloride is obtained.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:16])=O.[BH4-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C(O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:15]([N:6]2[CH2:7][C@H:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH2:9][C@H:5]2[CH2:3][OH:2])=[O:16])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (79.4 g: 205 mmole) in a mixture of tetrahydrofuran (200 ml) and ethanol (300 ml), sodium borohydride (14 g) is added in several portions under ice cooling. The mixture is stirred at room temperature for 4 hours. The reaction mixture is neutralized with conc. sulfuric acid, concentrated in vacuo to approximately a half volume, diluted with water, and extracted with ethyl acetate. The extract is successively washed with aqueous sodium hydrogen carbonate, water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=1:2) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (58.7 g). Yield: 81.7%.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:10]=1)=[O:8])C.O.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36](S(O)(=O)=O)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH2:43]([N:6]1[CH:5]=[CH:4][C:13]2=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:10]=[C:9]2[C:7]1=[O:8])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A mixture of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (2,2-diethoxyethyl)-amide (I-1A-1a; 528 mg, 0.92 mmol) and p-toluenesulfonic acid monohydrate (175 mg, 0.92 mmol) in toluene (5 ml) was heated to reflux in round bottom flask fitted with a Dean-Stark condenser. After 1 hour, the reaction mixture was cooled to room temperature, and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo. The crude material (0.49 g) was purified on a Biotage™ Flash 40S column using 10-20-40% ethyl acetate in hexanes as eluant to afford I-1A-1b as a solid (69 mg, 16%): +ESI MS (M+1) 480.1; 1H NMR (500 MHz, CD2Cl2) δ 7.50 (d, J=1.5 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.3, 2.1 Hz, 1H), 7.38-7.27 (m, 7H), 7.18 (d, J=8.7 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.42 (d, J=7.5 Hz, 1H), 5.21 (s, 2H).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[S:9][C:8]([C:10]#[N:11])=[C:7]([CH3:12])[CH:6]=1)=[O:4]>C(O)C>[OH:4][CH2:3][C:5]1[S:9][C:8]([C:10]#[N:11])=[C:7]([CH3:12])[CH:6]=1
Reactant: Cc1cc(C=O)sc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CO)sc1C#N
Reaction time: 0.08 h

Procedure:
5.75 g (152 mmol) of sodium borohydride were added portionwise at room temperature to a solution of 23 g (152 mmol) of 5-formyl-3-methylthiophene-2-carbonitrile in 300 ml of absolute ethanol. The reaction mixture was stirred for 5 minutes, concentrated under a water pump vacuum, taken up in ethyl acetate and extracted with 5% strength citric acid solution and with saturated sodium chloride solution, the organic phase was dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off at room temperature and under a water pump vacuum. This gave 24 g of the title compound as a dark red oil which still contained solvent and which was employed in the following reactions without further purification. 1H NMR (270 MHz, DMSO-d6): δ=2.4 (s, 3H), 4.7 (m, 2H), 5.9 (m, 1H), 7.0 (s, 1H).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[NH2:34][C:35]([NH2:37])=[S:36]>C(#N)C>[NH2:37][C:35]1[S:36][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:34]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NC(N)=S
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CC#N
Product: CCOC(=O)c1sc(N)nc1-c1ccccc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of ethyl 3-phenyl-3-oxopropionate (5.0 g, 26.0 mmol) in 100 mL of acetonitrile was added hydroxy(tosyloxy)iodobenzene (11.2 g, 28.6 mmol). The resulting suspension was stirred at 65° C. for 1 h at which time the reaction was a homogeneous solution. Thiourea (2.2 g, 28.6 mmol) was added and stirring was continued at 65° C. for 2 h. The mixture was cooled and concentrated, and the residue was taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated. The residue was triturated with ethyl ether to afford 4.9 g (70%) of the title compound as a yellow solid. 1H NMR (CDCl3) d 7.65 (m, 2H), 7.39 (m, 3H), 5.98 (broad s, 2H), 4.18 (q, 2H), 1.22 (t, 3H).
Reaction SMILES: FOC(F)(F)F.FOC(OF)(F)F.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].FC1C=CC(NS(C)(=O)=O)=CC=1.FC1C=C(F)C=CC=1NS(C)(=O)=O.FC1C=CC=C(F)C=1NS(C)(=O)=O>>[C:16]1([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Nc1ccccc1F
Agent: CS(=O)(=O)Nc1c(F)cccc1F
Agent: CS(=O)(=O)Nc1ccc(F)cc1
Agent: CS(=O)(=O)Nc1ccc(F)cc1F
Product: CS(=O)(=O)Nc1ccccc1

Procedure:
The procedure of Example 26 was repeated except that in place of the fluoroxytrifluoromethane, there was added bis-(fluoroxy)difluoromethane at a rate of 2.40 parts per hour for one hour. Analysis of the reaction product by liquid chromatographic techniques indicated 38% N-(2-fluorophenyl)methanesulfonamide, 12% N-(4-fluorophenyl)methanesulfonamide, 10% N-(2,4-difluorophenyl)methanesulfonamide and 1% N-(2,6-difluorophenyl)methanesulfonamide at 97% conversion.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=1.Cl[C:14]1[S:15][C:16]([Cl:20])=[C:17]([Cl:19])[N:18]=1.CO>CN(C)C=O.C(OCC)(=O)C.O>[Cl:19][C:17]1[N:18]=[C:14]([O:11][C:7]2[C:6]([CH3:12])=[CH:5][C:4]([NH2:3])=[C:9]([CH3:10])[CH:8]=2)[S:15][C:16]=1[Cl:20]
Reactant: Cc1cc(O)c(C)cc1N
Reactant: Clc1nc(Cl)c(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2nc(Cl)c(Cl)s2)c(C)cc1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
1.3 g (33 mmol) sodium hydride (60% in oil) were added portionwise to a solution of 4.1 g (30.0 mmol) of 4-amino-2,5-dimethylphenol in 30 ml of dimethylformamide. After the gas evolution has stopped, 5.6 g (30 mmol) of 2,4,5-trichloro-1,3-thiazole were added and the reaction mixture was stirred for 1 h at 100° C. At ambient temperature 0.5 ml methanol, 10 ml of water and 100 ml of ethyl acetate were added successively. The organic layer was separated, the watery layer extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate. Concentration in vacuo and column chromatographie (petroleum ether/acetone 4/1) yielded 4.8 g (16.6 mmol, 55%) of 4-[(4,5-dichloro-1,3-thiazol-2-yl)oxy]-2,5-dimethylaniline log P (pH=2.3)=3.4