Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@H:29]([CH3:30])[C@@H:28]2[C@@:5]([C:32]([OH:34])=[O:33])([CH2:6][CH2:7][C@@:8]3([CH3:31])[C@:13]4([CH3:27])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[C@H:19]([OH:25])[CH2:18][C@:17]5([CH3:26])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.IC.[C:37](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C@H:2]1[C@H:29]([CH3:30])[C@@H:28]2[C@@:5]([C:32]([O:34][CH3:37])=[O:33])([CH2:6][CH2:7][C@@:8]3([CH3:31])[C@:13]4([CH3:27])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[C@H:19]([OH:25])[CH2:18][C@:17]5([CH3:26])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of corosolic acid (2.0 g, 4.34 mmol), iodomethane (1 mL, 16 mmol), potassium carbonate (4.5 g, 32.6 mmol) and acetone (60 mL) was stirred at rt for 16 h. After completion of the reaction, the solids were filtered off and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel column using chloroform-methanol (10%) as eluent to furnish methyl corosolate (1.7 g, 83%), which was recrystallised from chloroform-hexane, m.p. 208-210° C.; IR (KBr): 3432, 2946, 2872, 1728, 1455, 1230, 1197, 1049 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.75 (3H, s, CH3), 0.83 (3H, s, CH3), 0.85 (3H, d, J=6.5 Hz, CH3), 0.94 (3H, d, J=5.7 Hz, CH3), 0.99 (3H, s, CH3), 1.03 (3H, s, CH3), 1.08 (3H, s, CH3), 2.23 (1H, d, J=11.0 Hz, H-18), 3.0 (1H, d, J=8.4 Hz, H-3), 3.60 (3H, s, —COOCH3), 3.62-3.71 (1H, m, H-2), 5.25 (1H, t, J=3.4 Hz, H-12); LCMS (negative ion mode): m/z 485 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:12]([CH3:14])[CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)I
Reactant: O=Cc1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of commercially available 2-fluoro-6-hydroxybenzaldehyde (3.000 g; 21.40 mmol), 2-iodopropane (10.919 g; 64.20 mmol), K2CO3 (5.918 g; 42.80 mmol), and Cs2CO3 (1.395 g; 4.28 mmol) in anh. DMF (63 ml) was stirred at rt, under nitrogen, for 16 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-fluoro-6-isopropoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 183.15 g/mol.
Reaction SMILES: [Na].[C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)(=[O:4])[CH3:3].Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH:20]=1)[NH2:19]>C(O)C>[NH2:19][C:18]1[CH:20]=[C:14]([S:12][C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:2](=[O:4])[CH3:3])=[CH:7][CH:8]=2)[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [Na]
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
Sodium (0.269 g) was added to ethanol (20 ml) and the resultant solution was allowed to cool to ambient temperature and 4-acetamidothiophenol (1.94 g) was added. The mixture was stirred for 5 minutes and 5-chloro-2-nitroaniline (2 g) was added. The mixture was then heated under reflux under argon for 3 hours and allowed to cool. The resultant solid was collected by filtration, washed with ethanol then dried to give the title compound (2.46 g) as a solid. NMR: 2.05 (s, 3H), 6.3 (dd, 1H), 6.6 (s, 1H), 7.4 (brs, 2H), 7.5 (d, 2H), 7.7 (d, 2H), 7.9 (d, 1H); MS (ESP+): 304 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>O>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([S:14]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)=[O:38])[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(Sc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.1 g (3.1 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate and 30 ml of dichloromethane were introduced into a round-bottomed flask, and 970 mg (3.1 mmol) of meta-chloroperbenzoic acid were then added. The entire contents were stirred at room temperature for two hours, the reaction medium poured into water, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica column eluted with dichloromethane. After evaporation of the solvents, 1 g (84%) of the expected ester was recovered.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[N:12]=2)=[CH:16][CH:17]=1
Reactant: NCCCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Product: COc1ccc(N(C)c2nc(NCCCCO)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (81 mg, 0.24 mmol) and 4-amino-butan-1-ol (69 μL, 0.75 mmol) by a procedure similar to Example 180, yielding a pale yellow oil (55 mg; 65%). 1H NMR (CDCl3) δ 7.48 (m, 1H), 7.38 (m, 1H), 7.12 (m, 2H), 6.91 (m, 2H), 6.81 (m, 1H),6.69 (m, 1H), 3.84 (s, 3H), 3.78 (t, J=6 Hz, 2H), 3.60 (m, 2H), 3.53 (s, 3H), 1.82 (m, 2H), 1.73 (m, 2H); LC-MS (ESI+; 353 ([M+H]+)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH:8]2[NH:12]C(=O)N[C:9]2=[O:14])=[CH:5][CH:4]=1.[OH-:17].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([C:9]([OH:14])=[O:17])[NH2:12])=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: COc1ccc(CC2NC(=O)NC2=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC(N)C(=O)O)cc1

Procedure:
A solution of 148 g. of 5-p-methoxybenzyl hydantoin and 188 g. of sodium hydroxide in one liter of water is heated at reflux for 25 hours. The solution is cooled and made acid to pH 1 with concentrated hydrochloric acid. The formed solid is separated by filtration, washed with water and dried to give the above named compound, mp. 255° C. dec.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[CH3:28]>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:30][CH2:31]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(C)ccc2C)CC1
Yield: 72 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2,5-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1>FC(F)(F)C(O)=O>[N:5]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=[CH:13][C:4]=1[CH:3]=[O:2]
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc2c(n1)NCCC2
Reaction time: 12.5 h

Procedure:
8-2 (10 g, 0.048 mol) was treated with trifluoroacetic acid (50 mL) and the resulting solution stirred under argon for 12.5 h. The TFA was removed at reduced pressure and the residue partitioned between sat. NaHCO3 and CH2Cl2. The organic layer was dried, concentrated and passed through a 3 in. pad of silica gel (10% acetone/CH2Cl2) and concentrated to afford 8-3 as a yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[N:10]1([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:19][CH:20]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1N
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (1.1 g, 5.3 mmol) in acetic acid (8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150° C. for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH 10. The resulting aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a grey solid (0.80 g, 73%). It was used in the next step without purification. MS (ES+): m/z 314 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C([O:32][CH2:33][C:34](Cl)=[O:35])(=O)C>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20]([C:33](=[O:32])[CH2:34][OH:35])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)CO)C1
Temperature: 4 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (0.25 g; prepared as described in Example 29) was dissolved in a mixture of methylene chloride (10 ml) and diisopropylethylamine (0.3 ml). The solution was cooled in an ice/water bath to 4° C. and acetoxyacetyl chloride (0.069 ml) added. The reaction mixture was stirred cold for two hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in 7M methanolic ammonia (10 ml) and the resulting solution stirred overnight. The solvent was evaporated and the residue purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) 98/2 to 92/8 The fractions containing the expected product were evaporated and the residue was triturated with diethylether to give the title product as a pale yellow solid (0.161 g, 61%); 3H NMR Spectrum: (DMSO-d6 @ 393K, 500 MHz) 2.10-2.40 (m, 2H), 3.50-3.70 (m, 3H), 3.70-3.85 (m, 1H), 3.95 (s, 3H), 4.05 (s, 2H), 5.15 (s, 1H), 7.15-730 (m, 2H), 7.30-7.45 (m, 1H), 7.50-7.70 (m, 1H), 7.85 (s, 1H), 8.40 (s, 1H), 9.20 (bs, 1H); Mass Spectrum: (M+H)+ 447.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]([N:22]3[CH2:29][CH2:28][C@:27]4([CH3:32])[C@H:30]([CH3:31])[C@H:23]3[CH2:24][C:25]3[CH:36]=[CH:35][C:34]([C:37]([NH:39][OH:40])=[NH:38])=[CH:33][C:26]=34)=[O:21])=[CH:19][C:14]=2[N:13]=[CH:12]1>>[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]([N:22]3[CH2:29][CH2:28][C@:27]4([CH3:32])[C@H:30]([CH3:31])[C@H:23]3[CH2:24][C:25]3[CH:36]=[CH:35][C:34]([C:37]5[N:38]=[CH:1][O:40][N:39]=5)=[CH:33][C:26]=34)=[O:21])=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=N)NO)cc3[C@]1(C)CCN2C(=O)c1ccc2[nH]cnc2c1
Reactant: CCOC(OCC)OCC
Product: C[C@@H]1[C@H]2Cc3ccc(-c4ncon4)cc3[C@]1(C)CCN2C(=O)c1ccc2[nH]cnc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of triethyl orthoformate (4 mL) and (2R,6R,11S)-3-(1H-benzoimidazole-5-carbonyl)-N-hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxamidine (0.25 g) is stirred at 100° C. for 6 h. After cooling to room temperature, the mixture is concentrated and the residue is purified by HPLC on reversed phase (water/MeCN/NH3) to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:33]3[N:37]=[CH:36][O:35][C:34]3=[S:38])=[CH:23][CH:22]=2)[C:7]([CH2:11][O:12][Si](C(C)(C)C)(C)C)=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(#N)C.C([O-])(O)=O.[Na+]>O>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:33]3[N:37]=[CH:36][O:35][C:34]3=[S:38])=[CH:25][CH:26]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2-n2ncoc2=S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-n2ncoc2=S)cc1
Yield: 50 %

Procedure:
A solution of 5-[4'-[[2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl)-1H-imidazol-1-yl]methyl][1,1'-biphenyl-2-yl]-1,3,4-oxadiazol-2[3H]-thione (100 mg) in 1:9 48% HF/acetonitrile (10 mL) was stirred at room temperature for 3 hours in a plastic flask. The reaction mixture was neutralized by the dropwise addition of saturated aqueous NaHCO3 (to pH 5) and was diluted with water. The resulting precipitate was collected by filtration and washed with water. Recrystallization from ethyl acetate gave pure 5-[4'-[[2-butyl-4-chloro-5-(hydroxymethyl)1H imidazol-1-yl]methyl][1,1'-biphenyl-2-yl]-1,3,4-oxadiazol-2[3H]-thione (40 mg, 50%), mp 193°-194° C. dec.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].[OH-].[Na+]>C(O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CCN=c1sc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCN=c1sc2ccccc2s1
Yield: 70.8 %

Procedure:
A solution of 3-[(1,3-benzodithiol-2-ylidene)amino]propanoic acid, ethyl ester (3.0g, prepared as described in Example 2) and sodium hydroxide (449 mg) in 120 ml of absolute ethanol is stirred at room temperature for 120 hours. The reaction mixture is concentrated in vacuo, and the resultant solid residue is washed with diethyl ether to remove unreacted starting material. The crude reaction product is dissolved in 50 ml of water, filtered through Celite, and the aqueous solution is then treated with 10% hydrochloric acid until the pH is 5. The resultant precipitate is collected by filtration and dried in vacuo at 60° C overnight. Recrystallization of the dried product from n-pentyl alcohol yields 1.9g of the title compound, melting point 203°-204° C.
Reaction SMILES: C([C:4]1[O:5][C:6]2[C:12]([Cl:13])=[CH:11][C:10]([F:14])=[C:9]([C:15]3[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1)(O)=O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Cl:13][C:12]1[C:6]2[O:5][CH:4]=[CH:8][C:7]=2[C:9]([C:15]2[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)=[C:10]([F:14])[CH:11]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C(=O)O)cc23)c1=O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3occc23)c1=O
Temperature: 210 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
0.29 g (0.74 mmol) of 3-(2-carboxy-7-chloro-5-fluorobenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 15 ml of quinoline, and 0.05 g (0.75 mmol) of copper powder was added thereto, followed by stirring at 210° C. for 15 minutes. Then, copper was removed by filtration, and the filtrate was poured into water and acidified by an addition of hydrochloric acid, and then extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.18 g (yield: 70%) of the desired product. Melting point: 178-179° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 24.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (87 mg, 0.18 mmol) obtained in step 2 and ethanesulfonamide (94 mg, 0.90 mmol), the title compound (25 mg, 25%) was obtained.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[N:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl>C(O)C>[CH3:21][C:17]1[CH:16]=[C:15]([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[N:13]=[N:12][C:11]([OH:14])=[CH:10][CH:9]=3)[CH2:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(C2(O)CCN(c3ccc(O)nn3)CC2)c1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(C2=CCN(c3ccc(O)nn3)CC2)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 2.9 parts of 6-[4-hydroxy-4-(3-methylphenyl)-1-piperidinyl]-3-pyridazinol, 30 parts of a hydrochloric acid solution 6N and 24 parts of ethanol was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated. Crushed ice was added and the whole was treated with concentrate ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (75%) of 6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)pyridinyl]-3-pyridazinol; mp. 179.0° C. (compound 270).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4]CC.CCN(CC)CC.[ClH:14].[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[N:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28]2)[CH2:24][CH2:23]1>CO>[ClH:14].[OH:15][CH:16]1[CH:17]([N:22]2[CH2:23][CH2:24][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28]3)[CH2:26][CH2:27]2)[CH2:18][C:19]2[C:20](=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:21]1
Reactant: OC1CCCCC1N1CCC2(C=Cc3ccccc32)CC1
Reactant: CCCCCC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: OC1Cc2ccccc2CC1N1CCC2(C=Cc3ccccc32)CC1

Procedure:
A biphasic mixture of the bromohydrin (1.14 g, 5.0 mmol) in 2M aq. NaOH (100mL) and CHCl3 (100 mL) was refluxed for 2.5 h. TLC (silica gel; 50% hexane-CH2Cl2) confirmed that formation of the epoxide was complete. The mixture was cooled to room temperature and the two layers were separated. The aq. phase was re-extracted with CHCl3 (2×30 mL) and discarded. The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield the crude epoxide as a pale yellow syrup which was redissolved in EtOH (30 mL) and Et3N (2 mL). Spiro[1H-indene-1,4'-piperidine]hydrochloride (1.11 g, 5.0 mmol) was added to this solution, and the resulting mixture was refluxed overnight. After 17 h, heating was stopped. The mixture was cooled to room temperature and concentrated to a residue in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and the solution was washed with satd aq. NaHCO3 (30 mL). The aqueous extract was washed with CH2Cl2 (30 mL) and discarded. The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated to a residue. The latter was dissolved in a minimum volume of CH2Cl2 and applied to a short column of silica gel which was subsequently eluted with 25% acetone-hexane. Concentration of the eluent yielded the product (0.91 g, 55%) as a brown syrup. The latter was estimated by tlc (silica gel, acetone(25):hexane (74):Et3N (1)) to be greater than 97% pure. The corresponding hydrochloride was prepared in MeOH as outlined for (11a) above, and recrystallized from isopropyl alcohol; mp 254°-257° C.; 1H NMR (CDCl3) δ1.46 (d, 2, piperidyl β-Heq., J= 12.8 Hz), 2.17 (m, 2, piperidyl β-Hax.), 2.86-3.49 (m, 8, tetrahydronaphthyl C1-H, C3-H, C4-H & piperidyl α-Hax.,eq.), 3.93-4.20 (m, 3, piperidyl α-Heq & C HOH), 6.79 (d, 1, indenyl C2-H, J=5.6 Hz), 6.90 (d, 1, indenyl C3-H, J=5.7 Hz), 7.03-7.42 (m, 8, aryl).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:39]([C:41]1[CH:46]=[CH:45][C:44]([N:47]=[C:48]=[O:49])=[CH:43][CH:42]=1)[CH3:40]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:39]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:49])[O:8][CH2:9][C@@H:10]([N:12]([CH3:20])[C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[CH3:11])=[CH:43][CH:42]=1)[CH3:40]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OC[C@H](C)N(C)C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)propan-2-yl(methyl)carbamate (301 mg, 1.0 mmol) in THF was added TBAF (1M in THF, 1.5 mL, 1.5 mmol, 1.5 equiv.) and the mixture was stirred for 1 h followed by quenched with saturated NaHCO3 and diluted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude oil, which was re-dissolved in THF (2.0 mL). To this THF solution were added DMAP and 4-ethylphenyl isocyanate. The reaction mixture was stirred for 30 min. LC/MS indicated the completion of the reaction and the mixture was filtered and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-2-(methyl(tert-butoxycarbonyl)amino)propyl 4-ethylphenylcarbamate (118 mg, 30% from 1). LRMS (M-Boc+H+) m/z 237.1.