Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl>[Br:25][C:10]1[NH:11][C:12]2[C:17]([C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2c[nH]c3ccccc23)cc1
Solvent: ClCCl
Product: COc1ccc(-c2c(Br)[nH]c3ccccc23)cc1

Procedure:
3-(4-methoxyphenyl)-1H-indole was dissolved in 4 ml DCM. NBS (0.9 eq) was added in small portions over 2 min. The solvent was concentrated and the crude product was purified using HPLC (MeCN/H2O gradient). 103.3 mg 2-bromo-3-(4-methoxyphenyl)-1H-indole was obtained as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[O:19]1[C:24]2[CH:25]=[CH:26][C:27](B(O)O)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>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>[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:2][C:3]3[N:4]=[C:5]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[S:6][C:7]=3[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
Ethyl 4-(bromomethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (109.4 mg, 0.326 mmol), 1,4-benzodioxane-6-boronic acid (91.0 mg, 0.506 mmol), tetrakis(triphenylphosphine)palladium(0) (43.0 mg, 0.0372 mmol), cesium carbonate (430 mg, 1.3 mmol), 1,4-dioxane (2.19 mL, 28.0 mmol) and water (43.8 uL, 2.43 mmol) were combined in a vial equipped with a stirbar. The vial was sealed and the atmosphere was replaced with nitrogen. The vial was sonicated for 1 minute then heated at 90° C. (heating block temperature) with stirring for 1 hour. The reaction was cooled to room temperature, the vial was opened and the contents were quenched into stirring saline. The quench mixture was transferred to a separatory funnel and extracted twice with ethyl acetate. The extracts were combined, washed with saline, dried over sodium sulfate, filtered, and concentrated in vacuo to leave an orange oil. The crude residue was purified by silica gel chromatography (gradient elution: ethyl acetate/hexane from 0/100 to 100/0) to give ethyl 4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (60 mg, 47% yield) as a white powder. LC/MS (FA) ES+ 391; 1H NMR (300 MHz, DMSO-d6) δ: 6.67-6.74 (m, 3H), 4.20 (q, 2H, J=7.1 Hz), 4.17 (s, 4H), 4.07 (s, 2H), 3.69-3.65 (m, 4H), 3.46-3.43 (m, 4H), 1.24 (t, 3H, J=7.1 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[O:8])[CH2:6][CH3:7].[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(#N)C>[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:2][CH2:3][NH:4][C:5](=[O:8])[CH2:6][CH3:7])[CH2:12][CH2:11]1
Reactant: OC1CCNCC1
Reactant: CCC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CCC(=O)NCCN1CCC(O)CC1

Procedure:
A mixture of N-(2-chloroethyl)propanamide (27.1 g, 0.20 mol), 4-hydroxypiperidine (20.2 g, 0.20 mol) and anhydrous sodium carbonate (10.6 g, 0.10 mol) in acetonitrile (120 ml) was stirred at reflux under nitrogen for 20 hours. Additional 4-hydroxypiperidine (20.2 g, 0.20 mol) was added and the mixture stirred at reflux for 3 days. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate and a minimum amount of water. The aqueous layer was saturated with sodium chloride and re-extracted several times with ethyl acetate. The organic extracts were combined, dried (Na2SO4), filtered and concentrated to give 13.1 g of crude product. Pure product was obtained by flash chromatography over silica gel and elution with 20% methanol-80% chloroform.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:14][CH:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:36][CH2:37][C:38](Cl)=[O:39].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:36][CH2:37][C:38]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:14][CH:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=2)=[O:39]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)[nH]c2c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of methyl 2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.48 g, 18.6 mmol), sodium acetate (1.68 g, 20.5 mmol) and acetic acid (1.17 ml, 20.5 mmol) in tetrahydrofuran (60 ml) was added dropwise chloroacetyl chloride (1.63 ml, 20.5 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was m washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-[2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate (7.90 g, yield 100%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[N:8]=2)[CH:6]=1.[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:4]2[N:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C@H:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:15])[N:8]=3)[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)[N:3]=2)=[CH:23][CH:24]=1
Reactant: OB(O)c1ccsc1
Reactant: C[C@H](Nc1nccc(-n2cc(Br)nc2-c2ccc(F)cc2)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nccc(-n2cc(-c3ccsc3)nc2-c2ccc(F)cc2)n1)c1ccccc1
Yield: 56.2 %

Procedure:
4-Bromo-2-(4-fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)imidazole (109 mg, 0.25 mmol), thiophene-3-boronic acid (35 mg; 0.27 mmol) and Pd(PPh3)4 (14 mg, 0.0125 mmol) are dissolved in dioxane (1.25 ml) and saturated Na2CO3 solution (0.33 ml, 0.5 mmol) and heated to 80 C for 18 h. The reaction mixture is poured on saturated Na2CO3 solution and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated and purified via preparative HPLC on LiChrospher RP-18 (Gilson HPLC-system; column tube: 125 mm×25 mm ID) with MeCN/water as elution system, 40:60 to 100:0 as gradient and a flow rate of 10 ml/min to yield the title product as colorless crystals (62 mg, 60%).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([OH:17])=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC1C=CC(C2C([C:33]([F:36])([F:35])[F:34])=CC=CN=2)=CC=1.ClC1C(C2C=CC(C)=CC=2)=NC=CC=1>>[F:34][C:33]([F:36])([F:35])[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([OH:17])=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Reactant: Cc1ccc(-c2ncccc2C(F)(F)F)cc1
Agent: Cc1ccc(-c2ncccc2Cl)cc1
Product: O=S1(=O)N=C(O)c2ccc(-c3ncccc3C(F)(F)F)cc21

Procedure:
The title compound was prepared using the procedures as described for the preparation of the product of Example 1B, substituting the product of Example 7A for the product of Example 1A. MS (DCI+) m/z 329 (M+H)+; 1H NMR (DMSO-d6) δ 7.77 (m, 1H), 7.94 (d, J 7.8, 1H), 8.05 (d, J 7.8, 1H), 8.17 (s, 1H), 8.40 (dd, J 1.3, 7.8, 1H), 8.97 (d, J 4.7, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:6][O:5][C:4](=[O:7])[CH:3]1[S:8][CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:18]=1[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.[O:32]1CCCC1.[OH-].[Na+].C(O)(=O)C>CO.O>[OH:5][CH2:6][C:2]([CH3:31])([CH3:1])[CH:3]([S:8][CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:18]=1[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[C:4]([OH:7])=[O:32]
Reactant: CC1(C)COC(=O)C1SCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(CO)C(SCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1)C(=O)O
Reaction time: 16 h

Procedure:
130 mg (0.303 mmol) of 4,4-dimethyl-3-((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methylthio)dihydrofuran-2(3H)-one were dissolved in 2 ml of methanol and 2 ml of tetrahydrofurane followed by the addition of 0.334 ml (0.334 mmol) of a 1N sodium hydroxide aqueous solution. The solution was stirred for 16 h. It was acidified down to an acid pH with acetic acid, and diluted with water until precipitation of a solid, which was then filtered and washed with water. 115 mg of 4-hydroxy-3,3-dimethyl-2-((3-((3-(trifluoromethyl)phenyl)-ethynyl)imidazo[1,2-a]pyridin-2-yl)methylthio) butanoic acid were obtained as a pale brown solid. LC-MS: m/z=447 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 12.69 (s, 1H), 8.77 (d, J=6.7 Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.70 (t, J=8.2 Hz, 2H), 7.54-7.41 (m, 1H), 7.16 (t, J=6.6 Hz, 1H), 4.81 (d, J=12.3 Hz, 1H), 4.70 (sl, 1H), 4.58 (d, J=12.3 Hz, 1H), 3.92 (s, 1H), 3.40 (s, 1H), 3.10 (d, J=10.4 Hz, 1H), 0.86 (s, 3H), 0.82 (s, 3H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8][C:7]3=[O:18])[CH2:29][CH2:28]1
Reactant: O=C1Nc2cccc3c2[C@@]1(CCCCBr)CCC3
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCC[C@@]23CCCc4cccc(c42)NC3=O)CC1
Yield: 83.4 %

Procedure:
(S)-2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (308 mg, 1.0 mmol), 4-(2-methoxyphenyl)piperazine (415 mg, 2.1 mmol) and potassium carbonate (280 mg, 2.0 mmol) in anhydrous N,N-dimethylformamide (10 ml) were stirred at room temperature for 18 hours. Then, ethyl acetate (80 ml) was added to the resulting reaction mixture, which was washed with water and saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent under reduced pressure. The resulting product was separated and purified by means of silica gel column chromatography, whereby 350 mg (yield 84%) of the above-described object compound could be obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].Br[CH:12]([F:21])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[F:21][CH:12]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: O=C(c1ccccc1)C(F)Br
Reactant: COc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1ccc(C)c(OC(F)C(=O)c2ccccc2)c1

Procedure:
Using the method described in Example 17, equimolar amounts of 2-hydroxy-4-methoxytoluene and α-bromo-2-fluoroacetophenone are refluxed in benzene in the presence of potassium carbonate to provide 2-fluoro-α-(2-methyl-5-methoxyphenoxy)acetophenone. Recrystallization from cyclohexane provides a tan solid, m.p. 57°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[C:4]([I:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1c(Cl)cccc1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(I)c1CBr
Temperature: 70 °C
Yield: 96 %

Procedure:
A mixture of 1-chloro-3-iodo-2-methylbenzene (11 g, 44 mmol) in 60 mL CCl4 was stirred at 70° C. and treated with 1-bromopyrrolidine-2,5-dione (12 g, 65 mmol) and dibenzoyl peroxide (1.1 g, 4.4 mmol) slowly. The resulting mixture was refluxed for 15 hours. The mixture was cooled to room temperature, filtered through a plug of Celite, and washed with 10% EtOAc/hexane. The organic was concentrated and purified by column chromatography (0-10% EtOAc/hexane) to give 14 g pink solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)=[O:4].[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][C:9]3[NH:10][C:11](=[O:13])[O:12][C:8]=3[CH:7]=2)=[O:4])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)oc2c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: O
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2[nH]c(=O)oc2c1

Procedure:
The title compound is prepared from 2-chloro-N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide (Example 142a) and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 210-212° C. (water)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[F:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([F:25])=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(F)c(F)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(F)c(F)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([C:8]1([CH3:22])[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17]C)[CH:14]=2)[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[CH2:1]([C:8]1([CH3:22])[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([OH:17])[CH:14]=2)[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(Cc1ccccc1)C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(Cc2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 180 °C
Yield: 34.8 %

Procedure:
2-Benzyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone (6 g.) is mixed with pyridine hydrochloride (60 g.) and the mixture is heated at 180° C. for 3 hours. The dark liquid is poured into water (1 l.) and the dark powdery product is collected and crystallized from acetic acid to obtain 2-benzyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2 g.), m.p. 219°-221° C. The product is identified by its nuclear magnetic resonance spectrum.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:27](O)=[O:28])[CH3:26])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:27]([N:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:28])[CH3:26])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)C1CCCCCCN1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCCCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 9.4 g of ethyl azacyclooctane-2-carboxylate in 400 ml of ethyl acetate add 17.0 g of N-benzyloxycarbonyl- (S) -alanine, N-hydroxysuccinimide ester. Stir the reaction mixture at room temperature for 20 hours and concentrate it in vacuo to give 1-[N-benzyloxycarbonyl-(S)-alanyl]azacyclooctane-2(R,S)-carboxylic acid, ethyl ester, as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.O1CCOCC1>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
1,1-Dimethylethyl 4-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-1-piperazinecarboxylate (may be prepared as described in Intermediate 10; 5.450 g, 13.28 mmol) was dissolved in DCM (80 ml) and then 4M hydrochloric acid in dioxane (33.2 mL, 133 mmol) was added at room temperature and the reaction mixture was stirred for two hours. The reaction mixture was partitioned between DCM and aqueous sodium bicarbonate (30 ml). The organic phase was washed with further sodium bicarbonate (2×20 ml) and water (2×20 ml). The aqueous phase (pH 1) was basified by adding sodium hydroxide then the aqueous phase was extracted with DCM (2×20 ml). The solvent was removed under vacuum to give the title compound (3.5 g) as a white solid.
Reaction SMILES: Br[CH:2]([C:26](=[O:28])[NH2:27])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([CH:23]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:10].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>O1CCCC1>[C:29]([S:31][CH:2]([C:26](=[O:28])[NH2:27])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([CH:23]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:10])(=[O:32])[CH3:30]
Reactant: COc1ccc(CC(Br)C(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CC(SC(C)=O)C(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
To 1.00 g of 5-(2-bromo-2-carbamoylethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 80 ml of tetrahydrofuran and 368 mg of potassium thioacetate under an atmosphere of argon, and the mixture was stirred for 6 hours at room temperature. Solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, which was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was crystallized from hexane-ethyl acetate, then the crystals were collected by filtration to obtain 904 mg of 5-(2-acetylthio-2-carbamoylethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as light brown crystals.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.[CH2:40]([N:47]=[C:48]=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH2:40]([NH:47][C:48](=[O:49])[N:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:16][CH:17]=1)[CH:23]1[C:32]2[N:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:26][CH2:25][CH2:24]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-[5,6,7,8-tetrahydro-8-quinolinyl]-1,4-benzenedimethanamine (140 mg, 0.257 mmol) in dichloromethane (5 ml) cooled to 0° C. was added dropwise, benzyl isocyanate (0.035 mL, 0.284 mmol). The reaction mixture was then allowed to stir at room temperature for two hours. The mixture was evaporated and the residue was purified by column chromatography on silica gel (3% methanol in dichloromethane as eluent) to afford the desired urea in an 81% yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.O.[C:17](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)nc1
Yield: 90.5 %

Procedure:
A solution of 6-hydroxynicotinic acid (1.00 g, 7.19 mmol) and concentrated sulfuric acid (0.47 ml) in methanol (80 ml) was refluxed for 10 hours then poured into water and sodium bicarbonate (1.45 g) was added. The solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica gel (eluting with 10%-20% methanol in dichloromethane) to give 6-hydroxynicotinic acid, methyl ester as a colourless solid (996 mg, 90%). The product was dissolved in concentrated aqueous ammonia solution and heated at 60° C. for 10 hours. Evaporation of the solvent in vacuo left a solid which was recrystallized from water to give 371 mg, 61% of the title compound as colourless needles.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][C:12]=2[O:21][CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CCCCCC.CCOCC>[C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][C:12]=2[O:21][CH3:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(CO)ccc1NS(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 109.5 %

Procedure:
A solution of methyl 4-phenylsulfonylamino-3-methoxybenzoate (1.5 g; prepared in Reference Example 37.) in THF (90 ml) was cooled to −78° C. in a stream of argon. The solution of diisobutylaluminum hydride (1.0 M) in hexane (22 ml) was added dropwise thereto. The mixture was stirred for 4 hours at −78° C. After the temperature increased to room temperature, the mixture was diluted with ether (100 ml). A saturated aqueous sodium sulfate (1.5 ml) was added thereto slowly. The mixture was stirred for 30 minutes, dried over, filtered and concentrated to give the title compound (1.5 g)