Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:15])(=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[SH:9].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[OH:22][C:16]1[CH:21]=[CH:20][C:19]2[S:9][C:8]3[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6](=[O:15])[C:18]=2[CH:17]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1c2ccccc2sc2ccc(O)cc12
Reaction time: 0.08 h

Procedure:
Concentrated sulphuric acid (300 ml) was slowly added to thiosalicylic acid (30.9 g) and the mixture was stirred for 5 minutes to ensure thorough mixing. Phenol (94 g.) was added slowly to the stirred mixture over a period of 30 minutes. After the addition, the addition was stirred at room temperature for 1 hour, then at 80° C. for two hours, after which it was left to stand at room temperature overnight. The resulting mixture was poured carefully with stirring into 10 times its volume of boiling water which was then boiled for a further 5 mins. The solution was cooled and filtered. The residue was recrystallised from acetone to give 2-hydroxythioxanthone as a yellow product.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[NH:25][C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.ClCCl>CN(C)C=O>[Br:1][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[NH:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]1)=[O:27])[CH2:10][CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCc3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCc3cc(Br)ccc32)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
N-Bromosuccinimide (2.6 g, 14.5 mmoles) was added to a solution of N-[2-(indolin-1-yl)-5-bromophenyl]-4-methyl-1-piperazinecarboxamide (5.0 g, 12.0 mmoles) in dimethylformamide (50 ml). The solution was stirred at room temperature for 15 minutes and at 60° C. for 15 minutes. The solution was cooled and poured into dichloromethane (500 ml). The layers were separated and the organic phase was washed with water (3×500 ml), brine (500 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography over silica gel (60 g, eluted with 4% methanol:96% dichloromethane, 1 l). The appropriate fractions were pooled and concentrated to give 4.8 g (84%) of product. Recrystallization from chloroform and hexane gave the analytical sample, mp 118°-119.5° C.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:17][N:18]([CH2:20][CH2:21][CH2:22]Cl)[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:19])[CH2:20][CH2:21][CH2:22][N:11]1[CH2:12][CH2:13][N:9]([N:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]1=[O:14]
Reactant: O=C1NCCN1N=Cc1ccccc1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCN(N=Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A near solution of 9.46 g (0.050 mole) of 1-[(phenylmethylene)amino]-2-imidazolidinone in 125 ml of dimethylformamide is treated portionwise with 2.0 g (0.050 mole) of NaH (60% dispersion in mineral oil) with the temperature rising to 30° C. The reaction is stirred at ambient temperature for 15 minutes with a solid forming. A 100 ml portion of dimethylformamide is added, to aid in stirring, and the mixture is stirred at 80° to 90° C. for 30 minutes. The mixture is cooled to ambient temperature and treated all at once with 12.2 g (0.100 mole) of dimethylaminopropyl chloride (prepared as described in Part I above). The resulting mixture is heated at 80° to 90° C. for 3 hours with near dissolution. The solvent is removed in vacuo. The residual semi-solid is dissolved in H2O (150 ml), and extracted with ethyl acetate (2×200 ml). The combined extracts are dried over MgSO4 and the solvent is removed in vacuo. The residual solid is washed with ether and air-dried to yield 4.8 g of 3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([CH3:12])[CH:3]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(F)ccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-Fluoro-2-methyl-1-(trifluoromethyl)benzene (5.6 mmol, 1 g) was dissolved in concentrated sulphuric acid (7 ml) and cooled to 0° C.; KNO3 (1 eq., 5.6 mmol, 566 mg) was added at to 0° C. in one pot and the mixture was stirred at to 0° C. for 4 hours. The crude mixture was poured onto ice and extracted with ethyl acetate; the organics were combined dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, 1.1 g, 88%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:21]2[CH2:22][CH2:23][C:19](=[O:24])[CH2:20]2)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Product: O=C1CC[C@@H](c2ccc(OCc3ccccc3)c(F)c2)C1
Yield: 68.6 %

Procedure:
[4-(Benzyloxy)-3-fluorophenyl]boronic acid (5.00 g, 20 mmol) and cyclopentenone (0.85 mL, 10 mmol) were used and treated in a similar manner to (Step 1) of (Example 3) to give the title compound (1.95 g, 68%).
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]>[Pd].C(O)C>[CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(CCC(=O)O)cc1
Yield: 99.9 %

Procedure:
An ethanol (250 ml) solution of 4-ethyl cinnamic acid (34.0 g, 0.191 mol) was hydrogenated at 60 psi over 10% Pd/C (2 g) for 2 hr. The mixture was filtered and concentrated in vacuo to give 3-(4-ethylphenyl)propionic acid as a white solid (34 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[C@H:13]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][C@@H:13]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: COc1ccc(O)cc1OC
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](O)c3ccccc3)CC2)c1
Product: COc1ccc(O[C@H](CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1OC

Procedure:
Prepared by Procedure B and Scheme B1 using 3,4-dimethoxyphenol and N-(3-{1-[(2R)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 503.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][O:26]C(=O)C)[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.[OH-].[Na+].Cl>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][OH:26])[S:20][CH:21]=3)[CH2:14][CH2:15]2)=[CH:2]1
Reactant: CC(=O)OCCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CCO)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 29.2 %

Procedure:
To 4-[4-(3-indolyl)piperidinomethyl]-2-(3acetoxypropionylamino)thiazole (1.1 g) were added ethanol (20 ml) and 1N aqueous solution of sodium hydroxide (2.6 ml) and the mixture was stirred at an ambient temperature for 3.5 hours. 1N hydrochloric acid (2.6 ml) was added thereto and ethanol was evaporated. The residue was extracted with a mixture of chloroform and methanol (10:1 V/V) and the extract was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1 V/V) to give 4-[4-(3-indolyl)piperidinomethyl]-2(3-hydroxypropionylamino)thiazole (290 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.[NH4+].[Cl-]>CO.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccccc2F)cc1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Into a 250 mL 3-necked round-bottom flask, was placed a solution of 1-fluoro-2-(4-nitrophenoxy)benzene (5 g, 21.44 mmol, 1.00 equiv) in methanol/H2O (2/1=V/V) (100 mL), and NH4Cl (1 g, 18.70 mmol, 0.87 equiv). This was followed by the addition of Fe (7 g, 5.83 equiv), in portions at 80° C. in 20 min. The resulting solution was stirred for 1 h at reflux in an oil bath. The reaction mixture was cooled in a water bath. The solids were filtered out and the filtrate was concentrated under vacuum. The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.2 g (73%) of 4-(2-fluorophenoxy)aniline as a light yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.2 %

Procedure:
To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.83 g) obtained in Reference Example 35 and ethyl acetate (20 mL) were added pyridine (1.80 mL) and acetic anhydride (2.27 g), and the mixture was stirred at room temperature for 19 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.55 g) as a colorless oil.
Reaction SMILES: [CH2:1]1[C:5](=[O:6])[N:4]([CH2:7][C:8]([NH2:10])=[O:9])[CH2:3][CH:2]1[OH:11].[C:12](Cl)(=[O:14])[CH3:13]>>[C:8]([CH2:7][N:4]1[CH2:3][CH:2]([O:11][C:12](=[O:14])[CH3:13])[CH2:1][C:5]1=[O:6])(=[O:9])[NH2:10]
Reactant: NC(=O)CN1CC(O)CC1=O
Reactant: CC(=O)Cl
Product: CC(=O)OC1CC(=O)N(CC(N)=O)C1

Procedure:
A mixture of 5.33 g oxiracetam and 44.3 ml acetyl chloride is heated at reflux for 15 min. After cooling, the solvent is evaporated in vacuo and the oil remaining is taken up in a little aqueous sodium bicarbonate, and solid sodium bicarbonate is added with stirring until neutrality is achieved. Most of the water present is removed by treating with methyl isobutyl ketone in vacuo, the residue is taken up with methylene chloride, dried with sodium sulphate and evaporated in vacuo. The oil remaining is triturated in isopropyl alcohol/diethyl ether and recrystallised from 20:80 isopropyl alcohol/isopropyl ether to give 1-carbamoylmethyl-4-acetoxy-2-pyrrolidone which when purified by chromatography melts at 84°-86° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33](Br)[CH:32]=1>>[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:32]=[C:33]([C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:16])[F:17])=[CH:13][C:8]=2[CH2:7][N:3]([C:4](=[O:6])[CH3:5])[CH2:1][CH3:2])[CH:34]=[C:35]([Cl:37])[CH:36]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(C)=O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: N-ethyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-acetamide and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([F:35])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:33][CH3:34])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]([C:29]([O:31]C)=[O:30])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1>C1COCC1.CO>[Cl:3][C:4]1[C:5]([F:35])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:33][CH3:34])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]([C:29]([OH:31])=[O:30])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
2N NaOH (1.3 ml, 2.66 mmol) was added to a solution of methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylate (14) (0.252 g, 0.53 mmol) in THF (5 ml) and methanol (1 ml). The reaction mixture was stirred overnight at room temperature and evaporated to dryness. The residues were dissolved in water (10 ml) and the solution acidified to pH6 with 2N HCl. The resulting solids were collected by filtration, washed with water (5 ml) followed by diethylether (5 ml) and dried under vacuum to give (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylic acid (15) as a cream solid (145 mg, 59%): 1H NMR Spectrum: (DMSO-d6) δ1.72-1.90 (2H, m), 2.20-2.31 (1H, m), 2.40-2.55 (1H+DMSO, m), 2.66 (3H, s), 2.84-2.94 (1H, m), 3.10-4.10 (2H, m), 3.95 (3H, s), 4.56-4.60 (1H, m), 7.18-7.25 (2H, m), 7.48-7.55 (2H, m), 8.05 (1H, s), 8.40 (1H, s); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][F:23])[CH2:17][CH2:16]1)=O)(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FCCN1CCNCC1

Procedure:
Trifluoroacetic acid (20 ml) was added to a mixture of 4-(tert-butoxycarbonyl)-1-(2-fluoroethyl)piperazine (3.7 g), triethylsilane. (8 ml) and methylene chloride (100 ml) and the resultant mixture was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was isolated, washed with diethyl ether and dried to give 1-(2-fluoroethyl)piperazine trifluoroacetic acid salt (6.0 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=2[C:7]=1[OH:16])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:27]>C(OCC)(=O)C>[NH2:27]/[C:4](/[C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1])=[C:6]1\[C:7](=[O:16])[C:8]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: O=C(c1ccccc1Cl)c1sc2ccc(Cl)cc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N/C(=C1/Sc2ccc(Cl)cc2C1=O)c1ccccc1Cl
Yield: 40 %

Procedure:
Prepared as in Example 1 from 2-(2-chlorobenzoyl)-5-chlorobenzo[b]thiophen-3-ol, phosphorus(V) chloride and concentrated aqueous ammonia with a yield of 40% of theory; m.p. 199°-201° C. (ethyl acetate).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][O:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:48]3[CH2:49][CH2:50][CH:45]([O:44][CH3:43])[CH2:46][CH2:47]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: COC1CCNCC1
Product: COC1CCN(C(=O)c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc23)CC1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 4-methoxypiperidine
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([C:36](=[O:38])[CH3:37])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1
Reactant: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3noc(C)n3)CC2)C1
Reaction time: 16 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.10 g, 0.24 mmol) and triethylamine (0.70 ml, 0.50 mmol) in dichloromethane (4.8 ml) was added acetyl chloride (0.019 ml, 0.26 mmol) at room temperature. After stirring for 16 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.003 g, 3%) as white solid. MS m/e: 427 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][CH:21]([CH3:24])[CH2:22][OH:23]>>[CH2:22]([O:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1)[CH:21]([CH3:24])[CH3:20]
Reactant: CC(C)CO
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(OCC(C)C)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methyl-propan-1-ol to give (1-isobutoxy-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 313 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[N:1]1[C:21]([NH2:22])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1Cl
Reactant: COc1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnn(-c3ccc(Cl)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2,4-dichloro-benzene (0.400 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.376 g, 1.2 eq) in ethanol (3 ml) kept under nitrogen, a solution of sodium methoxide (0.172 g, 1.5 eq) in ethanol (2 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (25 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (0.750 g) is purified by crystallization from a mixture of dichloromethane and hexane (1:1), to afford the title compound as white solid (0.315 g, 44% yield). M.p. 149.2-150.7° C.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C(=O)=O.[F:7][C:8]([F:34])([F:33])[S:9]([C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[CH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[C:17](=[C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:16]=2[CH:32]=1)(=[O:11])=[O:10]>CO.C(Cl)(Cl)Cl>[OH:3][CH:1]([N:29]1[CH2:30][CH2:31][C:26](=[C:17]2[C:16]3[CH:32]=[C:12]([S:9]([C:8]([F:34])([F:7])[F:33])(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]=3[CH:21]=[CH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]2=3)[CH2:27][CH2:28]1)[CH3:2]
Reactant: O=S(=O)(c1ccc2c(c1)C(=C1CCNCC1)c1ccccc1C=C2)C(F)(F)F
Reactant: C1CO1
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)N1CCC(=C2c3ccccc3C=Cc3ccc(S(=O)(=O)C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.244 g. of ethylene oxide of 30 ml. of methanol at dry-ice temperature is added to an ice cold solution of 2.55 g. of 4-(3-trifluoromethylsulfonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine in 15 ml. of chloroform and 75 ml. of methanol. The solution is stirred at ambient temperature overnight. A second quantity (0.25 g.) of ethylene oxide is added as before and the mixture is again stirred overnight. The mixture is concentrated to dryness and the residue is coevaporated in vacuo several times with acetonitrile. The product is recrystallized several times from acetonitrile to give (±)-1-hydroxyethyl-4-(3-trifluoromethylsulfonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 141°-144° C.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH:26](O)[CH2:27][CH3:28])[CH2:21]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][CH2:27][CH2:28][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH2:21]1
Reactant: CCC(O)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.213 g (1.5 mmol) of (3-cyclohexyl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.33 g).