Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].C([O:6][C:7](=O)[CH:8]=[CH:9][C@@H:10]1[CH2:14][C@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][N:11]1[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])C>C(O)C>[CH2:38]([O:37][C:35]([N:11]1[CH2:12][C@@H:13]([S:15][C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][C@H:10]1[CH:9]1[NH:3][NH:2][C:7](=[O:6])[CH2:8]1)=[O:36])[CH:39]=[CH2:40]
Reactant: NN
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C=CC(=O)OCC
Solvent: O
Solvent: CCO
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C1CC(=O)NN1
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
Hydrazine monohydrate (0.61 ml, 12.6 mmol) was dropwise added to a solution of 3-[(2S,4S)-N-allyloxycarbonyl-4-tritylthiopyrrolidin-2-yl]acrylic acid ethyl ester (1.53 g, 2.9 mmol) in ethanol (7.5 ml) under cooling with ice, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 2% methanol-chloroform) to obtain (2S,4S)-N-allyloxycarbonyl-2-(3-pyrazolidinon-5-yl)-4-tritylthiopyrrolidine (830 mg, yield: 51.1%). This compound was immediately dissolved in methylene chloride (10 ml). Then, triethylamine (0.24 ml, 1.7 mmol) and allyl chloroformate (0.18 ml 1.7 mmol) were dropwise added thereto under cooling with ice, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 ml). The organic layer was washed with water and a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 1% methanol-chloroform) to obtain (2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)-4-tritylthiopyrrolidine (592 mg, yield: 62%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCCCC=CC1CCCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCC1CCCCN1C(=O)OC(C)(C)C

Procedure:
A solution of N-Boc-2-(1-heptenyl)piperdine (3.92, 13.93 mmol) in 7 mL of ethanol was shaken under 58 psi of H2 pressure over 0.78 g Pd/C catalyst overnight, and then the mixture was filtered through Celite and concentrated to give 3.94 g (quantitative) of the product. No further purification was necessary. 1H NMR (250 MHz) δ4.20-4.15 (br s, 1 H), 3.99-3.85 (br d, 1 H), 2.79-2.70 (dt, 1 H), 1.59-1.25 (m, 21 H), 0.89-0.85 (t, 3 H); 13C NMR (62.7 MHz) 155.1 (s), 78.8 (s), 50.3 (s), 38.6 (s), 31.8 (s), 29.6 (s), 29.5 (s), 29.3 (s), 28.4 (s), 26.3 (s), 25.6 (s), 22.6 (s), 18.9 (s), 14.0 (s) ppm.
Reaction SMILES: [C:1]([O:4]CC)(=[O:3])[CH3:2].[C:7]1([NH:13][N:14]=[CH:15][C@@H:16]([C@H:18]([C@H:20]([CH3:22])[OH:21])[OH:19])[OH:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O:26][C:27](=[O:29])[CH3:28])(=O)C>CN(C)C1C=CN=CC=1.O>[C:7]1([NH:13][N:14]=[CH:15][C@@H:16]([C@H:18]([C@H:20]([C:22]([O:4][C:1](=[O:3])[CH3:2])([O:26][C:27](=[O:29])[CH3:28])[O:4][C:1](=[O:3])[CH3:2])[OH:21])[OH:19])[OH:17])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(C)=O
Reactant: C[C@H](O)[C@H](O)[C@@H](O)C=NNc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Product: CC(=O)OC(OC(C)=O)(OC(C)=O)[C@H](O)[C@H](O)[C@@H](O)C=NNc1ccccc1
Reaction time: 0.5 h

Procedure:
To the ethyl acetate solution of 5-deoxy-L-arabinose phenylhydrazone obtained in the step (3) of the preceding example, 9.0 g (0.074 mol) of 4-dimethylaminopyridine (DMAP) was added and dissolved therein. Then 120.82 g (1.183 mol) of acetic anhydride was added by dripping to the solution at an ambient temperature of 10° C. After stirring overnight at the same ambient temperature, 250 me of water was added to the solution, which was then stirred for 30 minutes. After allowing the solution to stand, it was separated into a water layer and an organic layer, and a 20% aqueous solution of sodium hydroxide was added to the organic layer up to its neutralization. Then after allowing the solution to stand, its organic layer was separated out and dried over anhydrous sodium sulfate. When the thus treated ethyl acetate solution was subjected to vacuum concentration, an ethyl acetate solution of triacetoxy-5-deoxy-L-arabinose phenylhydrazone was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:3]([C:4](=[O:5])[N:6]([CH3:7])[CH3:8])[CH:9]=1
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1cc(Br)ccc1NC(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
2-Amino-5-bromo-N,N-dimethyl-benzamide (2.00 g, 8.22 mmol), di-iso-propyl ethyl amine (6.5 ml, 37.32 mmol), 4-morpholinecarbonyl chloride (4.3 ml, 37.46 mmol), and chloroform (20 ml) were combined and stirred for 18 hours at 50° C. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (50% to 100% ethyl acetate in hexanes) to give 1.13 g (39%) of morpholine-4-carboxylic acid (4-bromo-2-dimethylcarbamoyl-phenyl)-amide. 1H-NMR (250 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.56-7.45 (m, 2H), 7.42 (t, J=9.3 Hz, 4H), 3.35-3.28 (m, 4H), 2.96-2.86 (m, 6H); MS: m/z 356.0+358.1 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH3:9])[NH:6][C:7]=1[CH3:8])[CH3:2].[C:10]([Cl:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[ClH:18].[CH2:1]([C:3]1[N:4]=[C:5]([CH2:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:17])[NH:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCc1nc(C)[nH]c1C
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Product: CCc1nc(CC(=O)c2ccccc2)[nH]c1C
Product: Cl

Procedure:
The compound is prepared as described in example X (step 4 and 5) with 1.00 g (8.05 mmol) 4-Ethyl-2,5-dimethyl-1H-imidazole (example XIII, step 1), 3.74 g (26.57 mmol) of benzoyl chloride and 2.85 g (28.18 mmol) of TEA in 20 ml acetonitrile. After reaction the solvent is evaporated under vacuum. The residue is extracted with toluene/water and the water phase is filtrated over a silica-layer. The solvent is evaporated under vacuum. The crude intermediate is directly transformed into 2-(4-Ethyl-5-methyl-1H-imidazol-2-yl)-1-phenylethanone hydrochloride. After the reaction the solvent is evaporated under vacuum. The residue is extracted with ethyl acetate/water. The water phase is concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O.FC1C=CC(C=O)=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(C=O)cc2)cc1[N+](=O)[O-]
Yield: 99.1 %

Procedure:
A mixture of 4-amino-3-nitrophenol (1.54 g; 10.0 mmol), 4-fluorobenzaldehyde (1.05 mL; 10.0 mmol) and Cs2CO3 (3.91 g; 12.0 mmol) in anhydrous dimethylsulfoxide (10 mL) was heated at 80 degrees Centigrade, under nitrogen. An additional portion of 4-fluorobenzaldehyde (0.050 mL; 0.50 mmol) was added after 1 hour and heating was continued. After 2 hours the mixture was cooled, poured into water and extracted three times with ethyl acetate. Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexanes), affording 2.56 g of 4-[(4-Amino-3-nitrophenyl)oxy]benzaldehyde as an orange solid. 1H NMR (400 MHz, CDCl3) delta ppm 6.11 (br. s, 2H), 6.90 (d, J=9.1 Hz, 1H), 7.04 (m, 2H), 7.20 (dd, J=9.0, 2.8 Hz, 1H), 7.86 (m, 2H), 7.89 (d, J=2.7 Hz, 1H), 9.93 (s, 1H) ppm. (M+H) 259, 2.33 min (LC/MS method A).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[C:7](OC(=O)C)(=[O:9])C.[CH2:14]1COC[CH2:15]1>>[CH3:14][CH2:15][CH2:6][CH2:5][O:4][C@H:3]([CH2:7][OH:9])[CH2:2][CH3:1]
Reactant: CC1CCOC1
Reactant: CC(=O)OC(C)=O
Reactant: C1CCOC1
Product: CCCCO[C@@H](CC)CO
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a 500ml flask was added 154.9 g of THF, 50 g of 3-methyl tetrahydofuran and 8.9 g of 70 wt. % HClO4 aqueous solution. The solution was cooled to 5° C., titrated 48.0 g of acetic anhydride over 30 minutes, and then stirred for 8 hours at 5° C. After quenching the solution with 160.5 g of 17 wt. % aqueous solution of sodium hydroxide and stirring, the contents of the flask are allowed to settle and the water layer is removed. 50 g of 30 wt. % aqueous solution of sodium hydroxide is added to the oil layer, followed by heating to 120° C. to distill off the unreacted monomer, then 150 g of n-butanol are added and the solution is refluxed for 3 hours and saponificate the contents. After the contents are settled and the water layer is removed, 100 g of water is added to the oil layer. After heating the contents to reflux with constant stirring for 15 minutes, the contents of the flask are allowed to settle and cool, and, after the water layer is removed, the oil layer is rinsed by water. The oil layer is further rinsed 3 times by water adjusted to pH 2 to 3 by hydrochloric acid, by water adjusted to pH 3 to 4 and by non treated water and then the water layer is removed. After that, the oil layer is dried using a vacuum pump (10 to 20 mm Hg pressure) with heating to 120° C. and then PTMG can be obtained. The obtained polymer is transferred to the 100 ml standard bottle and the color number (JIS K-1557) is measured.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:15]([C:16](O)=[O:17])=[C:14]([Cl:19])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:3][C:16]([C:15]1[C:6]([Cl:5])=[C:7]([CH:12]=[CH:13][C:14]=1[Cl:19])[C:8]([O:10][CH3:11])=[O:9])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Yield: 100 %

Procedure:
2 drops of dimethylformamide and 11.90 g (0.1 mol) of thionyl chloride were added to a solution of 5.00 g (0.02 mol) of methyl 2,4-dichloro-3-hydroxycarbonylbenzoate and 50 ml of dry toluene. The solution was heated under reflux for 4 hours. Removal of the solvent by distillation gave 5.35 g of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([CH2:27][C:28]([OH:30])=O)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:27][C:28]([NH:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN(c1ccccc1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN(c1ccccc1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
The mixture of rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetic acid (70 mg, 0.159 mmol), cyclohexylamine (19 mg, 0.191 mmol) EDC.HCl (36 mg, 0.191 mmol), HOBt (26 mmg, 0.191 mmol) and DIPEA (25 mg, 0.191 mmol) in acetonitrile (3 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated and the residue was purified with chromatography to give 45 mg of rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide as a yellow solid. MS m/z 522 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH2:19][C:20]([O:22]CC)=[O:21])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH2:19][C:20]([OH:22])=[O:21])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)OCC)ccc2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)O)ccc2c1OCO2

Procedure:
To ethyl 2-(4-carbomethoxy-2-propylphenoxy)-3,4-methylenedioxyphenylacetate (Step A of Example 56) (2.04 g, 5.10 mmol) in MeOH (40 mL) was added 5N NaOH (8 mL). The rapid reaction was followed immediately by TLC to monitor mono deesterification. The reaction was quenched with 9N HCl (4.5 mL) after loss of the ethyl ester and before methyl ester saponification. A saturated solution of NaHCO3 was added to the reaction until it was basic and the MeOH was removed in vacuo. The residue was partitioned between Et2O and water collecting the product in the aqueous phase and removing impurities with the organic phase. The aqueous phase was then acidified with 9N HCl (pH=1) and the product extracted into EtOAc. The solution was dried over MgSO4, filtered and the solvent removed. Yield=1.78 g (4.78 nmole, 94%) rf=0.16 (80:10:1/CHCl3 :MeOH:NH4 OH).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:23][CH2:22][N:21]3[C:14](=[CH:15][C:16]4[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=43)[C:13]2=[O:26])=[CH:10][C:9]([F:27])=[CH:8][C:7]=1[C:28]1[CH:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][C@@H:45]([CH3:47])[N:44]([CH:48]4[CH2:51][O:50][CH2:49]4)[CH2:43][C@@H:42]3[CH3:52])=[CH:37][N:36]=2)[C:31](=[O:53])[N:30]([CH3:54])[CH:29]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH3:52][C@H:42]1[CH2:43][N:44]([CH:48]2[CH2:51][O:50][CH2:49]2)[C@H:45]([CH3:47])[CH2:46][N:41]1[C:38]1[CH:39]=[CH:40][C:35]([NH:34][C:32]2[C:31](=[O:53])[N:30]([CH3:54])[CH:29]=[C:28]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:23][CH2:22][N:21]5[C:20]6[CH2:19][C:18]([CH3:24])([CH3:25])[CH2:17][C:16]=6[CH:15]=[C:14]5[C:13]4=[O:26])[CH:10]=[C:9]([F:27])[CH:8]=3)[CH:33]=2)=[N:36][CH:37]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of 116a (150 mg, 0.20 mmol) and lithium hydroxide (48 mg, 2.0 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (2×10 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 116 (57 mg, 41%) as white solid. MS: [M+H]+ 696.3. 1H NMR (500 MHz, CDCl3) δ 8.60 (dd, J=2.0, 6.5 Hz, 1H), 8.02 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.50-7.49 (m, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 6.96 (dd, J=2.5, 9.0 Hz, 1H), 6.83-6.81 (m, 2H), 4.77-4.74 (m, 2H), 4.66-4.62 (m, 2H), 4.57-4.55 (m, 1H), 4.33-4.31 (m, 1H), 4.23-4.14 (m, 3H), 3.92-3.89 (m, 1H), 3.78-3.76 (m, 1H), 3.71 (s, 3H), 3.22-3.20 (m, 1H), 2.93-2.91 (m, 1H), 2.75-2.73 (m, 2H), 2.58 (s, 2H), 2.52 (s, 3H), 1.97-1.90 (m, 2H), 1.28 (s, 6H), 0.91 (d, J=5.5 Hz, 6H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Cl:14][C:15]1[CH:16]=[C:17]([S:22]([NH:25][CH2:26][P:27](=[O:44])([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:24])=[O:23])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(N(CC)CC)C>O1CCCC1.[Cu].II.CC(O)=O>[Cl:14][C:15]1[CH:16]=[C:17]([S:22]([N:25]([CH2:26][P:27](=[O:44])([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:23])=[O:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: O=P(CNS(=O)(=O)c1cc(Cl)cc(Cl)c1)(OCc1ccccc1)OCc1ccccc1
Agent: [Cu]
Agent: II
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=P(CN(c1ccc2ccccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
89 mg 2-naphthaleneboronic acid are added to a mixture of 130 mg dibenzyl [(3,5-dichloro-phenylsulphonylamino)-methyl]-phosphonate and 100 mg molecular sieve (4 Å) in 8 ml of tetrahydrofuran. Then 47 mg copper-II-acetate and 72 μl triethylamine are added and the reaction mixture is stirred for 24 hours at ambient temperature. For working up the reaction mixture is filtered. The filter cake is washed with tetrahydrofuran and the filtrate is evaporated down in vacuo. The flask residue is divided between concentrated aqueous ammonia solution and methylene chloride. The aqueous phase is extracted with methylene chloride and the combined organic phases are washed with 1 N sodium hydroxide solution, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])=[CH:12][CH:11]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C@@H:18]([CH3:19])[NH2:20])=[CH:12][CH:11]=1
Reactant: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 110.3 %

Procedure:
1,1-dimethylethyl [(1R)-2-({6-[(2,5-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 35, 60 mg) was dissolved in 4 mL of dry dichloromethane. To this solution, at 0° C., were added dropwise 40 equivalents of TFA (0.480 mL). The reaction was stirred for 3 hours 30 at 0° C. The reaction mixture was evaporated and then purified by SCX on a 5 g cartridge. 3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with CV of methanolic ammonia (1N). Evaporation of the volatiles, afforded the title compound (49 mg)
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1cc(Cl)ccc1C
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: Cc1ccc(Cl)cc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (9.5 g) was added at room temperature diethyl malonate (4.5 g) and then added little by little 4-(5-chloro-2-methylphenyl)-3-buten-2-one (5.5 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (15 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (15 ml) for 15 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-chloro-2-methylphenyl)cyclohexane-1,3-dione (2.9 g) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[F:6][C:7]1([F:58])[CH2:12][CH2:11][CH:10]([C:13]2[C:22]3[C@@H:21](O)[CH2:20][C:19]([CH3:25])([CH3:24])[CH2:18][C:17]=3[N:16]=[C:15]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[N:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([CH2:44][OH:45])([CH3:43])[CH2:41][OH:42])=[CH:34][N:33]=4)[CH2:28][CH2:27]3)[C:14]=2[C@@H:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[CH2:9][CH2:8]1>COC(C)(C)C>[CH3:1][S:2]([O:5][C@H:21]1[CH2:20][C:19]([CH3:24])([CH3:25])[CH2:18][C:17]2[N:16]=[C:15]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]4[N:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([CH2:41][OH:42])([CH3:43])[CH2:44][OH:45])=[CH:34][N:33]=4)[CH2:30][CH2:31]3)[C:14]([C@@H:46]([F:57])[C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:55])([F:54])[F:56])=[CH:49][CH:48]=3)=[C:13]([CH:10]3[CH2:11][CH2:12][C:7]([F:6])([F:58])[CH2:8][CH2:9]3)[C:22]1=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(OCC(C)(CO)CO)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Solvent: COC(C)(C)C
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCC(C)(CO)CO)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](OS(C)(=O)=O)C1
Yield: 50.7 %

Procedure:
Reactions similar to those of Example 3 were performed except for using 4.5 μl (0.069 mmol) of methanesulfonic acid instead of 47% hydrobromic acid salt and using 2.5 ml of tert-butyl methyl ether instead of methyl ethyl ketone, and from 51.8 mg (0.069 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 19, 29 mg of the title compound was obtained as a white powder (yield: 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([OH:17])[C:15]#[CH:16]>CN(C=O)C.[Cu]I.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>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[C:16]#[C:15][CH2:14][OH:17]
Reactant: C#CCO
Reactant: COc1ccc2nccc(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COc1ccc2nccc(C#CCO)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of 8-bromo-2-methoxy-[1,5]naphthyridine (4.0 g, 16.7 mmol, prepared as in WO 2006/032466) and propargylalcohol (1.9 g, 33.5 mmol) in DMF (50 mL) and TEA (10.16 g, 100 mmol) was degassed by bubbling N2 through for 10 min. CuI (0.318 g, 1.6 mmol) and Pd(PPh3)2Cl2 (0.588 g, 0.84 mmol) were added and the brown solution was stirred at rt overnight. The mixture was partitioned between water and EtOAc and the org. layer was washed several times with water and a sat. NH4Cl solution, dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 1:1, EA) followed by crystallization from ether gave the coupling product as a beige solid (1.95 g, 54% yield).