Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[N:26][CH:27]=1.O>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1)[O:19][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:30][CH:29]=2)=[N:26][CH:27]=1
Reactant: FC(F)(F)Oc1ccc(-c2ccc(CCl)cn2)cc1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
15 mg (0.60 mmol) of 95% sodium hydride were added at 0° C. to a solution of 116 mg (0.50 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 144 mg (0.50 mmol) 5-chloromethyl-2-(4-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether. The residue was purified by chromatography on silica (eluent: ethyl acetate/n-heptane 4:1) to give 136 mg (56%) of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17]C1C=C2C(=CC=1)N=CC(C(OCC)=O)=C2O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:17])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1O
Product: CCOC(=O)c1cnc2ccc(F)cc2c1Cl

Procedure:
The title compound was prepared following the procedure described in Step 2 for the synthesis of 3a using 2b instead of 2a. 1H NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.08 Hz), 4.51 (2H, q, J=7.08 Hz), 7.63 (1H, m), 8.02 (1H, dd, J=9.52, 2.68 Hz), 8.15 (1H, dd, J=9.27, 5.37 Hz), 9.15 (1H, s). m/z 254.6 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][C@@H:17]1[C:30]([O:32]C)=[O:31].[OH-]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][C@@H:17]1[C:30]([OH:32])=[O:31]
Reactant: COC(=O)[C@H]1CN(CCCc2cccs2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4cccs4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
A solution of 0.37 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)propyl]piperidine-3-carboxylate in 6 cm3 of dioxane, to which dioxane had been added 1.6 cm3 of N aqueous hydroxide, was stirred at a temperature in the region of 60° C. for 20 hours. After evaporating the solvents under reduced pressure (5 kPa) at a temperature in the region of 45° C., the residue obtained was taken up in 20 cm3 of water and then the aqueous phase was washed with 20 cm3 of ethyl ether. After separating the ether by settling, the aqueous phase was neutralized with 1.6 cm3 of N hydrochloric acid and then extracted with 2 times 30 cm3 of ethyl acetate. The combined extracts were dried over magnesium sulfate. The organic solution, after filtration, was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.21 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1 -[3-(thien-2- yl)propyl]piperidine-3-carboxylic acid was obtained in the form of a foam with a beige color which melts at approximately 60° C. with softening.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[BrH:23]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([Br:23])=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Br
Reactant: CCCCn1c(=O)c2[nH]c([N+](=O)[O-])nc2n(CCCC)c1=O
Product: CCCCn1c(=O)c2[nH]c(Br)nc2n(CCCC)c1=O

Procedure:
1,3-Di-n-butyl-8-bromo xanthine was prepared from 1,3-di-n-butyl-8-nitro xanthine (0.5 g, 0.0016 mol) and concentrated hydrobromic acid (8 ml) using the procedure as described in Example 15. The title product was obtained after recrystallisation from ethanol, yield 0.4 g (91%), m.pt. 178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:7]=2[C:6]([C:16]([O:18]C)=[O:17])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:7]=2[C:6]([C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: CCCc1ccc2c(C(=O)OC)ccc(OC)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCc1ccc2c(C(=O)O)ccc(OC)c2n1
Yield: 45.5 %

Procedure:
A mixture of methyl 8-methoxy-2-n-propylquinoline-5-carboxylate (1.0g, Reference Example 27), potassium carbonate (0.8 g), methanol (30 ml), and water (2 ml was refluxed for 5 hours. The solution was concentrated, then diluted with water and then washed with diethyl ether. The pH of the aqueous phase was adjusted to 6 by addition of hydrochloric acid (6M). The resulting cream precipitate was washed with water and then dried at 60° C. to give the title compound (0.43 g) as a cream coloured solid, m.p. 214-217° C. [Elemental analysis:— C, 67.00; H, 6.32; N, 5.53%. Calculated for C14H15NO3.0.25H2O:— C, 67.30; H, 6.06; N, 5.61%].
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[CH3:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Reactant: Cc1cccc(CC(=O)O)c1
Product: Cc1cccc(CC(=O)Nn2nc(S(=O)(=O)c3ccccc3)c3ccccc3c2=O)c1

Procedure:
The product from Example 68B and 2-(3-methylphenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (s, 1H), 8.54-8.57 (m, 1H), 8.37-8.40 (m, 1H), 8.08-8.13 (m, 1H), 7.98-8.03 (m, 3H), 7.78-7.83 (m, 1H), 7.66-7.70 (m, 2H), 7.23 (t, J=7.5
Reaction SMILES: ClC1C([C@@H]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])C)=CC2C(=C(Cl)C=CC=2)N=1.C([Sn](CCCC)(CCCC)C1SC=NC=1)CCC.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]1(=[O:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[NH:14]1
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cncs1
Solvent: C1COCCO1
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.2000 g, 0.5388 mmol), 5-(tributylstannyl)thiazole (0.4032 g, 1.078 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.06226 g, 0.05388 mmol) in 1,4-dioxane (4.490 mL, 0.5388 mmol) was stirred at 100° C. After 94 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 7 min as eluent to give 24(S)-1-(8-chloro-2-(thiazol-5-yl)-quinolin-3-yl)ethyl)isoindoline-1,3-dione as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (1 H, s), 8.83 (1 H, s), 8.30 (1 H, d, J=0.8 Hz), 8.13 (1 H, dd, J=8.2, 1.2 Hz), 7.99 (1 H, dd, J=7.6, 1.4 Hz), 7.71-7.82 (4 H, m), 7.60-7.69 (1 H, m), 6.03 (1 H, q, J=7.2 Hz), 1.88 (3 H, d, J=7.0 Hz); LC-MS (ESI) m/z 420.1 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C([O:14][C:15]([C:17]1[CH2:18][N:19]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([F:27])=[C:22](Cl)[N:21]=2)=[O:16])C>N1C=CC=CC=1>[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:22]3[N:21]=[C:20]4[C:25]([CH:26]=[C:17]([C:15]([OH:16])=[O:14])[CH2:18][N:19]4[C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[F:36])=[CH:24][C:23]=3[F:27])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1=Cc2cc(F)c(Cl)nc2N(c2ccc(F)cc2F)C1
Reactant: C1COC2(CCNCC2)OC1
Solvent: c1ccncc1
Product: O=C(O)C1=Cc2cc(F)c(N3CCC4(CC3)OCCCO4)nc2N(c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
In a reaction similar to that of Step 1, Example 387, into oven-dried glassware maintained under dry N2 were placed 0.622 g (3.96 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane, from Step 4 Example 196, 0.500 g (1.3 mmol) of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester, and 15 mL of dry pyridine. The reaction was stirred at room temperature for 5 hours, then the solvent was removed by evaporation. The residue was dissolved in 50 mL of methylene chloride, which was washed with 50 mL of 5% sodium bicarbonate and 50 mL of water, dried over anhydrous sodium sulfate, filtered and dried. The product was purified by recrystallization from ethanol/water, isolated by filtration and dried under vacuum to afford 0.576 g of the title compound, mp 177°-178° C., MS (DCl/NH3) M/Z 504 (M+H) (base). Analysis calculated for C25H24F3N3O5 : C, 59.64; H, 4.80; N, 8.35. Found: C, 61.13; H, 5.09; N, 8.36.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:10][CH2:11][Cl:12]>>[Cl:12][CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][C:2]([CH3:1])([OH:8])[CH2:3][CH2:4]1
Reactant: CC1(O)CCNCC1
Reactant: ClCCBr
Product: CC1(O)CCN(CCCl)CC1

Procedure:
4-methylpiperidin-4-ol (made via literature methods) and 1-bromo-2-chloroethane are reacted using the procedure for Example OO to afford 1-(2-chloroethyl)4-methylpiperidin-4-ol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>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(NCC)C>[CH3:15][Si:16]([C:19]#[C:20][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(C#C[Si](C)(C)C)cc2)cc1

Procedure:
In a flask having its atmosphere completely displaced with nitrogen were charged 19 g of 4,4'-diiodobiphenyl, 1.31 g of bis(triphenylphosphine)palladium dichloride, 0.094 g of cuprous iodide and 500 ml of diethylamine. The temperature was elevated to 30° C. under stirring, and 11.04 g of trimethylsilylacetylene was added to the mixture, followed by allowing the mixture to react for 4.5 hours to obtain 4,4'-di(trimethylsilylethynyl)biphenyl. Hydrolysis of this product yielded 4,4'-diethynylbiphenyl.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[CH2:11][C:10]2[C:5](=[C:6]([Cl:15])[C:7]([Cl:14])=[C:8]([O:12]C)[CH:9]=2)[C:4]1=[O:16])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[CH2:17]([C:3]1([CH2:1][CH3:2])[CH2:11][C:10]2[C:5](=[C:6]([Cl:15])[C:7]([Cl:14])=[C:8]([OH:12])[CH:9]=2)[C:4]1=[O:16])[CH3:18]
Reactant: CCC1(CC)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CCC1(CC)Cc2cc(O)c(Cl)c(Cl)c2C1=O

Procedure:
A stirred suspension of 2,2-diethyl-5-methoxy-6,7-dichloro-1-indanone (4.0 g., 0.014 mole) and aluminum chloride (4.7 g., 0.035 mole) in heptane (150 ml.) is refluxed for one hour and cooled. The heptane is decanted from the reaction mixture and the solid residue is treated with water (200 ml.) and concentrated hydrochloric acid (20 ml.). The 2,2-diethyl-5-hydroxy-6,7-dichloro-1-indanone which separates (3.7 g.) melts at 184° C. after recrystallization from butyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]>CCO.C1COCC1.[Pd]>[NH2:9][C:5]1[C:6]([OH:8])=[CH:7][C:2]([F:1])=[C:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1cc(N)c(O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of 1-(2-fluoro-4-hydroxy-5-nitro-phenyl)-ethanone (3 g, 15.7 mmol) in EtOH (30 mL) and THF (6 mL) was added 10% Pd/C (1.5 g, 1.4 mmol) and the reaction mixture was stirred at ambient temperature under an atmosphere of H2 for 2 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 1-(5-amino-2-fluoro-4-hydroxy-phenyl)-ethanone as black solid (2.5 g, 94%), which was used in the next step directly without further purification. 1H NMR (DMSO-d6, 400 MHz): δ 7.01 (d, J=8.0 Hz, 1H), 6.48 (d, J=12.4 Hz, 1H), 2.39 (d, J=4.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccn1
Product: COc1ccccc1C1(N[C@@H](Cc2ccccn2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 878 mg of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.55 g of the compound obtained in Step 84-2 as starting materials, 0.38 g (Isomer A, pale yellow amorphous) and 0.61 g (Isomer B, pale yellow amorphous) of the respective diastereoisomers of the title compound sere obtained by a similar method to Step 4-2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Na+].[I-].[SH:9][C:10]1[NH:14][N:13]=[N:12][CH:11]=1>CO>[CH2:2]([S:9][C:10]1[NH:14][N:13]=[N:12][CH:11]=1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: Sc1cnn[nH]1
Reactant: C=CCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: C=CCCCSc1cnn[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.3 %

Procedure:
5-bromopent-1-ene (10 mmol) and NaI were dissolved in 30 ml MeOH and stirred at room temperature for 12 h. 10 mmol 5-mercapto-1H-1,2,3-triazole (sodium salt) was added to above solution and further stirred for 24 hours. After the solvent MeOH was evaporated in vacuum, a mixture of hexane and ethyl acetate (1/1 in volume) 100 ml was added and stirred for 5 minutes. The precipitate was removed by filtration. The solvent in the filtrate was removed in vacuum. The residual was separated with a Si gel column (solvents: 1 ethyl acetate/1 hexane in volume). 0.8 g product was obtained as colorless oil. Yield: 47%. 1H NMR (CDCl3): 11.14 (1H, brs.), 7.69 (1H, s), 5.77 (1H, m), 5.03 (2H, m), 2.95 (2H, t), 2.17 (2H, m), 1.74 (2H, m).
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15][CH3:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl.O>[Br:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15]([CH3:16])=[O:25])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4]
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CSc1cc(C)nc(S(C)=O)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a solution of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (100 mg,0.311 mmol) in chloroform (2 ml) was added a solution of m-chloroperbenzoic acid (50 mg, 0.327 mmol) in chloroform (0.5 ml), and stirred at room temperature for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:acetone=1:1) to provide 21.4 mg (yield 20%) of 2-bromo-N-[2(methanesulfinyl)-6-methyl-4-(methylthio)-3-pyridyl]acetamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH2:15]1COCC1>CO.S(=O)(=O)(O)O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCOc2cc(F)ccc21
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1CCOc2cc(F)ccc21
Temperature: 55 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
7-Fluoro-3,4-dihydro-2H-chromene-4-carboxylic acid (346 mg, 1.76 mmol) was diluted with (THF) 2 mL, methanol (2 mL) and 4 drops of sulfuric acid. The reaction was heated at 55° C. and stirred for 12 hours. The reaction was cooled to ambient temperature, diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (366 mg, 98.7% yield).
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C
Yield: 936.7 %

Procedure:
In analogy to example 1 were reacted 6.36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol with 4.38 g (2 mmol) of lauroyl chloride and 2.02 g (2 mmol) of triethylamine in toluene to give 9.4 g (94%) dodecanoic acid 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester as yellowish liquid.
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH3:15])[N:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[CH2:7][CH2:6]1)C.C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27].O>CN(C=O)C>[NH2:27][C:26]1[N:28]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][N:11]([CH3:15])[C:12]=3[C:13]=2[N:25]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1nn(C)c2c1CCC(=CN(C)C)C2=O
Agent: O=C(O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 164.8 %

Procedure:
To a solution of 16.62 g (60 mmol) of ethyl 6-[(dimethylamino)methylene]-7-oxo-1-methyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 0.5 L of DMF, 27 g (150 mmol) of guanidine carbonate was added. The mixture was stirred at 110° C. overnight. After cooling the mixture was poured into water (2.5 L) and stirred for 30 minutes. The precipitate was filtered, washed with water and dried to yield 26.83 g of title compound (91%).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58][CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58][CH:59]1[CH2:64][CH2:63][N:62]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:61][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Clc1ccccc1SC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Sc2ccccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.04 g, 0.00014 mol) in DMF (1 mL) was added DIPEA (0.05517 g, 0.00043 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0326 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride (0.0449 g, 0.00017 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.054 g (84%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chlorophenylsulfanyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 455.12 (M+1)+, 83.96%, 1H NMR (DMSO-d6): δ 13.65 (s, 1H), 8.1 (s, 1H), 7.8 (d, 2H), 7.5 (m, 4H), 7.38 (t, 2H), 7.24 (t, 2H), 7.15 (s, 1H), 4.2 (m, 3H), 3.85 (m, 1H), 3.65 (m, 1H), 3.25 (m, 1H), 3.0 (m, 1H), 2.0 (m, 2H), 1.56 (m, 1H), 1.4 (m, 1H).
Reaction SMILES: Cl.NO.[Br:4][C:5]1[C:10]([CH:11]=O)=[C:9]([F:13])[C:8]([O:14][CH3:15])=[C:7]([F:16])[CH:6]=1.CC[N+:19](S(N=C(OC)[O-])(=O)=O)(CC)CC>CN(C=O)C>[Br:4][C:5]1[C:10]([C:11]#[N:19])=[C:9]([F:13])[C:8]([O:14][CH3:15])=[C:7]([F:16])[CH:6]=1
Reactant: COc1c(F)cc(Br)c(C=O)c1F
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Product: COc1c(F)cc(Br)c(C#N)c1F
Temperature: 150 °C

Procedure:
Add hydroxylamine hydrochloride (608 mg, 8.8 mmol) to a solution of 6-Bromo-2,4-difluoro-3-methoxy-benzaldehyde (2.0 g, 7.96 mmol) in anhydrous DMF (4 ml). Heat the mixture to 150° C. for 2 h. Add water to the cooled mixture and extract the product with EtOAc (×2). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate. Dissolve the concentrate in anhydrous THF and add 3 equivalent of the Burgess reagent ((methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt). Heat the mixture under reflux under nitrogen atmosphere overnight. Concentrate to yield a crude residue. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19]C)[N:3]=1.C(OC(N1CCCCC(N)C1)=O)(C)(C)C.C(OC([N:43]1[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45][CH2:44]1)=O)(C)(C)C>>[NH:43]1[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[OH:19])[N:3]=2)[CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Reactant: COc1ccc(Cl)cc1-c1nc(Cl)c2ccccc2n1
Agent: CC(C)(C)OC(=O)N1CCCCC(N)C1
Product: Oc1ccc(Cl)cc1-c1nc(NC2CCCNCC2)c2ccccc2n1

Procedure:
The title compound was prepared using a method analogous to that described in Synthesis 52, replacing 4-chloro-2-(2-methoxyphenyl)quinazoline with 4-chloro-2-(5-chloro-2-methoxyphenyl)quinazoline in Synthesis 52-A and tert-butyl-3-aminoazepane-1-carboxylate with tert-butyl-4-aminoazepane-1-carboxylate in Synthesis 52-B.