Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]1[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[C:21]1=[O:31]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCCCCCCOc1ccc2ccccc2c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCOc1ccc2ccccc2c1

Procedure:
1-Chloro-8-(2-naphthyloxy)octane (4.75 g) and potassium phthalimide (4.2 g) were heated in dimethylformamide (25 ml) at 120° for 4 hours. The solution was then cooled, added to water, and extracted with methylene chloride. The extracts were then dried and evaporated to afford N-[8-(2-naphthyloxy)octyl]phthalimide as a gum. This material was refluxed for 16 hours in ethanol (150 ml) containing 85% aqueous hydrazine hydrate (3 ml). The solution was cooled and water (450 ml) and 10% aqueous potassium hydroxide (50 ml) were added. The resultant solution was extracted with hexane; the extract was dried and evaporated to afford the title compound as an oil (hydrochloride mp 169°-170°).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4](=[S:21])[NH:3]1.[NH2:22][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[OH:33][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4](=[S:21])[NH:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCN(c2ccc(C=C3SC(=S)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-[4-(4-Oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Example 34) (0.16 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in 1,2-dichloroethane (10 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N sodium hydroxide (NaOH) and then poured into a saturated aqueous sodium bicarbonate (NaHCO3). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried and concentrated. The residue was purified by preparative thin layer chromatography (16% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp>220° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.50–1.70 (m, 2 H), 1.90–2.10 (m, 2 H), 2.60–3.40 (m, 7 H), 3.90–4.20 (m, 3 H), 6.70–7.15 (m, 6 H), 7.30 (d, J=8.8 Hz, 2 H); 7.38 (d, J=8.8 Hz, 2 H); MS (ES) m/z: 470.0 (MH+); HRMS Calcd. for C24H27N3O3S2(M+): 469.1494. Found: 469.1488.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[CH2:9][CH2:8][NH:7]1.[CH3:15][N:16]=[C:17]=[S:18]>C(#N)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[CH2:9][CH2:8][N:7]1[C:17](=[S:18])[NH:16][CH3:15]
Reactant: CN=C=S
Reactant: c1coc(C2NCCc3[nH]cnc32)c1
Solvent: CC#N
Product: CNC(=S)N1CCc2[nH]cnc2C1c1ccco1

Procedure:
Operating as in Example 14, 12 g of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (oil) are obtained from 18.4 g of histamine dihydrochloride and 16.6 ml of furfural. A solution of 1.89 g of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1.1 g of methyl isothiocyanate in 20 ml of acetonitrile is refluxed for 5 h. The solution is cooled and filtered: 1.54 g of the title compound, m.p. 200°, are collected.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[C:8](OC(=O)C)(=[O:10])[CH3:9].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A mixture of thiophen-2-ylmethanamine (600 mg, 5.30 mmol), DMAP (130 mg, 1.06 mmol, 0.2 equiv) and acetic anhydride (648 mg, 6.36 mmol, 1.2 equiv) in DCM (20 mL) was stirred at room temperature for 2 h. Water was added and the reaction was extracted with EA. The combined organic layers were dried (Na2SO4), filtered. The filtrate was concentrated to afford the compound N-(thiophen-2-ylmethyl)acetamide (745 mg, 91%). LC-MS (m/z)=156 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=1)#[N:2]
Reactant: Sc1ccccc1
Reactant: N#Cc1ncc(Cl)nc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ncc(Sc2ccccc2)nc1C#N
Yield: 47.8 %

Procedure:
2,3-Dicyano-5-chloropyrazine (0.83 g; 0.005 mole) was dissolved in 25 ml of acetone. The solution was cooled to 0° to 3° C., and with stirring, a solution prepared from 0.55 g (0.005 mole) of thiophenol, 0.21 g (0.005 mole) of sodium hydroxide, 1 ml of water, and 20 ml of acetone was added dropwise over the period of 10 minutes. Then, the reaction mixture was worked up in the same way as in Example 7, and recrystallized from benzene to afford 0.57 g (yield 48%) of 2,3-dicyano-5-(phenylthio)pyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([OH:18])=O)[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([Cl:27])=[O:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1c(C(=O)O)nnn1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)Cl)nnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carboxylic acid (830 mg, 3.13 mmol) in dichloromethane (3 mL) was added DMF (50 μL) followed by oxalyl chloride (546 μL, 6.26 mmol) dropwise. After 5 min, the ice bath was removed and the mixture was stirred at room temperature for 1 h. CH2Cl2 was removed in vacuo to give 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carbonyl chloride as a white solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:41]5[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:34])[CH3:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 59.3 %

Procedure:
Following general procedure II, (S)-tert-butyl(1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]pyridin-2-yl}piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (82 mg, 0.30 mmol) to afford the crude product (72 mg) which was carried forward without any purification: ESI MS m/z 607 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C:15]1[S:19][N:18]=[N:17][C:16]=1[CH3:20].O.ClCCl>ClCCl>[CH3:8][S:9]([O:13][CH2:14][C:15]1[S:19][N:18]=[N:17][C:16]=1[CH3:20])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnsc1CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nnsc1COS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 10.0 ml of triethylamine (72.6 m mol) and 4.1 ml of methanesulfonyl chloride (53 m mol) was added successively to a solution of 6.27 g of 5-hydroxymethyl-4-methyl-1,2,3-thiadiazole (48.16 m mol) in dichloromethane (50 ml) at −30° C. After stirring for 30 minutes, the mixture was poured into water-dichloromethane while the pH was kept between 8.5-9.0. The aqueous layer was separated, the organic layer was washed with saturated sodium hydrocarbonate, washed with dil-hydrochloric acid brine, dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo to afford 5-methanesulfonyloxymethyl-4-methyl-1,2,3-thiadiazol (9.8 g).
Reaction SMILES: C(OC[C:6]1[O:7][C:8]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:9]=2[CH:10]=1)(=O)C.C(=O)([O-])[O-:18].[K+].[K+].C(OCC)(=O)C>CO>[F:16][C:11]1[C:9]2[CH:10]=[C:6]([OH:18])[O:7][C:8]=2[C:14]([F:15])=[CH:13][CH:12]=1
Reactant: CC(=O)OCc1cc2c(F)ccc(F)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cc2c(F)ccc(F)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
2-Acetoxymethyl-4,7-difluorobenzofuran (252 mg) was dissolved in 5 ml methanol, 455 mg potassium carbonate was added thereto at room temperature, and the mixture was stirred for 2 hours at the same temperature. Ethyl acetate was added to the reaction solution, and the organic layer was washed with brine. It was dried over anhydrous magnesium sulfate and then evaporated, and the resulting residue was subjected to silica gel chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 161 mg 4,7-difluoro-2-hydroxybenzofuran as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Br)cn1
Yield: 98.7 %

Procedure:
To a solution of 2-amino-5-bromopyridine (89.87 g, 0.5194 mol) in toluene (500 mL) was added 2,5-hexanedione (85.0 mL, 0.724 mol). The reaction flask was equipped with a Dean-Stark apparatus and the solution heated to reflux for 14 h. The cooled reaction solution was extracted with H2O (2×200 mL). The organic layer was added directly to a plug of SiO23″l×2″w and eluted with toluene (250 mL). This treatment removes a significant amount of color from the crude product. The resulting eluent was concentrated to a light amber oil, which solidified upon cooling to provide 128.76 g (99%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[O:27][CH:28]=[C:29]([CH2:31][CH3:32])[N:30]=4)=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5].[OH-].[Li+]>O1CCCC1.CO.O>[CH2:31]([C:29]1[N:30]=[C:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH:4]([CH3:5])[C:3]([OH:35])=[O:2])[CH:7]=[CH:8]4)=[C:21]([O:33][CH3:34])[CH:22]=2)[O:27][CH:28]=1)[CH3:32]
Reactant: CCc1coc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)OC)c3)c(OC)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1coc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)O)c3)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
2-(5-{3-[4-(4-Ethyl-oxazol-2-yl)-2-methoxy-phenoxy]-propoxy}-indol-1-yl)-propionic acid methyl ester (Example 62, 129.7 mg, 0.27 mmol) was dissolved in a solution of tetrahydrofuran (2 mL), methanol (1 mL), and water (2 mL). Lithium hydroxide (32.45 mg, 1.36 mmol) was added and the mixture was stirred at rt for 2 h. The solution was concentrated, diluted with water (5 mL), and acidified with 1N HCl. The resulting white precipitate was collected by filtration and dried to give the title compound (100.1 mg, 79.5%). LC/MS m/z 465.1 (M+H)+; RT 3.25 min. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.47 (dd, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 7.28 (d, 1H), 7.11 (d, 1H), 7.06 (d, 1H), 6.77 (dd, 1H), 6.34 (d, 1H), 5.24 (q, 1H), 4.19 (t, 2H), 4.12 (t, 2H), 3.82 (s, 3H), 2.52 (m, 2H), 2.20 (m, 2H), 1.68 (d, 3H), 1.19 (t, 3H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:21]([C:23]([S:42]([CH3:45])(=[O:44])=[O:43])([CH2:27][CH2:28][N:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][C:30]1=[O:41])[C:24]([OH:26])=O)[CH3:22].[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53].Cl.CN(C)CCCN=C=NCC>ClCCl.O>[CH2:21]([C:23]([S:42]([CH3:45])(=[O:43])=[O:44])([CH2:27][CH2:28][N:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][C:30]1=[O:41])[C:24]([NH:53][O:52][CH:47]1[CH2:48][CH2:49][CH2:50][CH2:51][O:46]1)=[O:26])[CH3:22]
Reactant: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
Diisopropylethylamine (35 uL, 0.2 mmol, 2.1 equiv) and 1-hydroxyl benzotriazole monohydrate (27 mg, 0.18 mmol, 1.9 equiv) were added sequentially to a solution of 2-ethyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)butanoic acid (34 mg, 0.09 mmol, 1.0 equiv) in dichloromethane (2 mL) at room temperature. After 30 min, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (15 mg, 0.12 mmol, 1.3 equiv) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (26 mg, 0.13 mmol, 1.4 equiv) were added, and the reaction was allowed to stir overnight. Water (2 mL) was added, the organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography (1:1-0:1 heptane/ethyl acetate) to provide a colorless oil (45 mg, 100%). MS (LCMS) m/z 461.8 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][OH:18])[C:10]=3[OH:19])[N:8]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>C1COCC1>[C:29]([O:18][CH2:17][C:11]1[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]([N:7]2[N:6]=[C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]3=[N:8]2)[C:10]=1[OH:19])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: C=C(C)C(=O)Cl
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: -5 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 3.98 g (13.0 mmol) 2-(5-chloro-2H-benzo[d][1,2,3]triazol-2-yl)-6-(hydroxymethyl)-4-methoxyphenol in 60 ml anhydrous THF. Triethylamine (6.4 ml) was added and the mixture was cooled to −10-0° C. Methacryloyl chloride (1.62 g, 15.5 mmol) was added dropwise and the mixture was stirred for 1 hr at −10-0° C. followed by 20 hours at ambient temperature. The solid was filtered and rinsed with 100 ml diethyl ether. The organic layer was washed with 1 N HCl and water, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to yield a yellow oil which was recrystallized in ethanol to give 1.73 g (34%) of a light yellow solid. 1H NMR (CDCl3) delta: 11.00 (s, 1H, Ar—OH), 7.92 (s, 1H, Ar—H benzotriazole), 7.88 (s, 1H, Ar—H phenol), 7.87 (d, 1H, Ar—H benzotriazole), 7.45 (d, 1H, Ar—H benzotriazole), 7.06 (s, 1H, Ar—H phenol), 6.21 (s, 1H, C═C—H trans), 5.62 (s, 1H, C═C—H cis), 5.38 (s, 2H, Ar—CH2), 3.89 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH2:9]([C:11]1[CH:19]=[C:18]([C:20]([F:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])[CH:17]=[C:16]([CH2:30][CH3:31])[C:12]=1[C:13](Cl)=[O:14])[CH3:10]>>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:13](=[O:14])[C:12]2[C:11]([CH2:9][CH3:10])=[CH:19][C:18]([C:20]([F:29])([C:21]([F:24])([F:22])[F:23])[C:25]([F:26])([F:27])[F:28])=[CH:17][C:16]=2[CH2:30][CH3:31])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1C(=O)Cl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1C(=O)Nc1cccc(N)c1

Procedure:
N-(3-Amino-phenyl)-2,6-diethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide was prepared from benzene-1,3-diamine and 2,6-diethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (Example I4) using the same procedure. 1H-NMR (CDCl3, 400 MHz): 7.4 (m, 3H), 7.22 (s, 1H), 7.15 (t, 1H), 6.72 (dd, 1H), 6.52 (dd, 1H), 2.80 (q, 4H), 1.30 (t, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([OH:34])(=O)=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[CH2:35]([NH:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37]>>[CH2:35]([N:38]([CH2:39][CH2:40][CH3:41])[S:31]([C:5]1[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1)(=[O:34])=[O:32])[CH2:36][CH3:37]
Reactant: CCCNCCC
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Product: CCCN(CCC)S(=O)(=O)c1cc(OC)c(OC)cc1/C=C/c1nc2c(c(=O)n(CCC)c(=O)n2CCC)n1C
Yield: 39.9 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 2.68 ml (19.6 mmol) of dipropylamine. The resulting crude crystals were recrystallized from cyclohexane/toluene to give 450 mg (yield 40%) of Compound 3 as a pale yellow powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:14]([O:15][CH3:16])=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>ClCCl>[C:24]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([O:3][CH3:2])[C:14]([O:15][CH3:16])=[CH:13][C:7]=2[CH2:8][CH2:9]1)(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: COc1cc2c(cc1OC)CCNCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At ambient temperature, 70 g (287.2 mmol) of the product obtained in Step 2 are dissolved in 1200 mL of dichloromethane, and then 100 mL (718 mmol/2.5 eq.) of triethylamine are added all at once. The mixture is brought to 0° C. and a solution of 25.8 mL (315.9 mmol/1.1 eq.) of acryloyl chloride in 270 mL of dichloromethane is poured in dropwise, maintaining the temperature at about 0° C. After 2 hours at 0° C., the mixture is stirred at ambient temperature overnight. Washing with 750 mL of water, 750 mL of 1N hydrochloric acid and 750 mL of water and then drying over magnesium sulphate are then carried out. After filtration and evaporation, the residue is chromatographed over 3.2 kg of silica (eluant: dichloromethane/ethanol: 95/5), followed by recrystallisation from isopropanol. After filtration over a frit and drying in vacuo at 50° C., the desired product is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([F:8])=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([F:8])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Yield: 33 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-fluoropyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave—20° C., 24 hours) to afford 2-(2-chloro-5-fluoropyrimidin-4-ylamino)-N-methyl-benzamide as a white solid in 33% yield. Mp: 225° C. (dec); MS: 281.23 (M+H); 1H NMR (chloroform-d): δ 11.78 (br s, 1H), δ 8.80 (d, J=8 Hz, 1H), δ8.11 (s, 1H), δ 7.60 (t, J=8 Hz, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.15 (t, J=8 Hz, 1H), δ 6.31 (br s, 1H), δ 3.06 (dd, J=2.5 Hz, 3H).
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.C([OH:24])C>>[OH:24][C:16]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]=[CH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:2]=1
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: CCO
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(N=Cc2cccc3ccccc23)c1O
Temperature: 70 °C

Procedure:
3.44 g (20.0 mmol) of 2-hydroxy-1-naphthaldehyde was dissolved in 50 ml ethanol under heating, and 2.14 g (20.0 mmol) of m-toluidine was added. After stirring under reflux at 70° C. for 1 hour, completion of the reaction was confirmed by TLC. The solution was concentrated with an evaporator to about 30 ml, whereupon a crystal was formed, which was filtered by Kiriyama funnel. Drying under reduced pressure at 25° C. for 24 hours gave 2-hydroxy-1-naphthylmethylidene-3-methylaniline (hereinafter, also referred to as “HNMT”) as a yellow crystal (4.43 g, 85%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C[Si](C)(C)[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl>[N:9]1([CH2:8][CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:2]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C[Si](C)(C)Oc1ccc(C=O)cc1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a stirred solution of 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (2.89 g, 10.7 mmol) in THF (30 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (7 mL, 10.2 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min before 4-trimethylsilyloxybenzaldehyde (2.08 g, 10.7 mmol) was added. The mixture was allowed to warm to rt during 20 min and quenched with water. Extraction with CH2Cl2, drying (MgSO4), filtration and evaporation provided the crude diarylmethanol which was dissolved in CH2Cl2 (30 mL) and stirred with triethylsilane (4 mL) and TFA (5 mL) for 16 h at rt. Evaporation gave 3.0 g (84%) 4-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-phenol. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent) to give the title product after purification by preparative HPLC (Gilson) (35%, oil).