Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:18][CH2:17][C@H:16]([S:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:14][CH2:15][C@H:16]([S:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[O:38])[CH2:17][CH2:18]2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(/C=C/C=C/[C@H]2CC[C@H](SCc3ccc(Cl)cc3)CC2)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(Cc1ccc(Cl)cc1)[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.08 h

Procedure:
In 20 ml of methylene chloride were dissolved 211 mg (0.48 mmol) of 4-chlorobenzyl trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexyl sulfide, and 104 mg (0.48 mmol) of m-chloroperbenzoic acid (purity: 80%) were added to the solution at 0° C. followed by stirring of the resulting mixture for 5 minutes. An aqueous sodium sulfite solution and ethyl acetate were added to the reaction mixture and the organic layer was washed with an aqueous sodium hydrogencarbonate solution and an aqueous NaCl solution. After the mixture was dried, the crude product obtained by evaporation of the solvent was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 168 mg (yield: 77%) of the title compound having a melting point of 212 to 214° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:19][C:16]1[S:15][C:14]([C:12]2[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example B.3) (0.25 g, 0.6 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.157 g, 0.71 mmol) according to the general procedure III. Obtained as a yellow solid (0.083 g, 32%). MS (ISP) 433.2 [(M+H)+]; mp 99° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15][CH3:16])=[C:7](CC=O)[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2].[CH3:24][Si](I)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:9][C:8]2[O:15][CH:16]=[CH:24][C:7]=2[C:6]=1[C:20]([CH3:21])([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1CC=O
Reactant: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1c(C(C)(C)C)cc2occc2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Acetoxy-3,5-di-tert-butyl-2-formylmethylanisole (16 g) was dissolved in dichloromethane (100 ml) and trimethylsilyl iodide (7.1 ml) was added dropwise to the solution under cooling with ice. After stirring the mixture at room temperature for 1 h, a saturated aqueous solution of sodium thiosulfate was added and the mixture was subjected to extraction with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butylbenzofuran quantitatively (14.3 g) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH:30][CH3:31]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([N:30]([CH3:31])[CH3:29])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: CNC
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)N(C)C)C1(C)C

Procedure:
The product from Example 173 and dimethylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.28-1.33 (m, 2H), 1.37-1.46 (m, 1H), 1.57 (s, 9H), 1.57-1.70 (m, 3H), 2.01-2.10 (m, 1H), 2.62-2.67 (m, 2H), 2.74-2.83 (m, 1H), 2.83 (s, 3H), 3.05 (s, 3H), 3.33-3.39 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 422 (M+H)+. Anal. calcd. for C23H39N3O2S: C, 65.52; H, 9.32; N, 9.97. Found: C, 65.26; H, 9.15; N, 9.88.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:43].C(OCC)C>C(Cl)Cl>[ClH:43].[NH2:8][C@@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc4)[C@H](F)C3)C2=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@@H](N)C(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 44 %

Procedure:
To a solution of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (0.025 g, 0.043 mmol) in DCM (1.5 mL) at −20° C. was added HCl in diethyl ether (2.5 ml, 2.50 mmol, 1.0 M). The reaction mixture was slowly warmed to rt over 10 min and then allowed to stir at rt for 19 h. The solvent was then removed in vacuo to provide a pale yellow semisolid. The crude product was then purified by RP-HPLC on a Sunfire C18 (250×20 mm) 5 μm column using a gradient of 10% solvent B to 75% solvent B over 12 minutes at 15 mL/min where solvent A=0.05% HCl in water and solvent B=acetonitrile. Active fractions were concentrated by lyophilization to provide 10.2 mg (44%) of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-amino-3-methylbutanoate hydrochloride, the titled compound of example 2 as an off-white solid. LC-MS (Method A) RT=2.20 min, (M+H)+=482.2. 1H NMR: (400 MHz, DMSO-d6) δ ppm 8.64-8.78 (m, 3H) 7.38-7.46 (m, 2H) 7.23 (d, J=8.53 Hz, 2H) 7.18 (s, 4H) 5.04-5.26 (m, 1H) 4.42 (d, J=9.54 Hz, 3H) 4.17-4.23 (m, 2H) 3.29-3.40 (m, 4H) 3.19-3.28 (m, 2H) 2.30 (s, 6H) 2.04-2.19 (m, 2H) 1.11 (dd, J=12.55, 7.03 Hz, 6H). 19F NMR (376 MHz, DMSO-d6) δ −183.904.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][NH:13]1)=[S:11].C(N(CC)CC)C.C.[C:26](Cl)(Cl)=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[N:12]2[N:13]([CH2:14][O:15][CH2:16][CH2:17]2)[C:26](=[O:27])[S:11]1
Reactant: S=C(Nc1ccc(Cl)cc1Cl)N1CCOCN1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1sc(=Nc2ccc(Cl)cc2Cl)n2n1COCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.8 g (6.2 mmol) N-(2,4-dichlorophenyl)tetrahydro-4H-1,3,4-oxadiazine-4-carbothioamide was dissolved in 30 mL toluene and 1 mL triethylamine in the presence of a small quantity of activated charcoal at 0°-5° C. 3.49 g (6.81 mmol) phosgene as 20% solution in 30 mL toluene was added dropwise over 1.5 h. The reaction mixture was then left to warm up to room temperature and stirred overnight. The activated charcoal was removed by filtration and the solvent evaporated in vacuo. The desired product was isolated after chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:21](OCC)=[O:22].CC[O-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21][OH:22])[C:14](=[O:20])[CH2:15]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A solution of 0.27 g (0.9 mmol) of 9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one in 2.0 mL of THF was stirred at rt and 0.70 mL (8.7 mmol) of ethyl formate was added followed by 1.0 mL of EtOH and 0.78 mL of a 21 wt % solution of NaOEt in EtOH. The reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was concentrated by rotary evaporation, quenched with sat. aq. NH4Cl and extracted with CHCl3. The organic layer was dried over MgSO4, filtered and concentrated to afford 0.25 g (86%) of 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one as an orange solid. 1H NMR (300 MHz, CDCl3) δ 14.11 (s, 1H), 8.24 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 4.85 (s, 1H), 4.32 (m, 1H), 2.58 (dd, J=19.8, 7.7 Hz, 1H), 2.17 (d, J=19.8 Hz, 1H), 2.00-1.76 (m, 2H), 1.61 (m, 5H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:12]2[C:8](=[N:9][NH:10][C:11]2=[O:13])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[O:13]=[C:11]1[NH:10][N:9]=[C:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[N:12]12
Reactant: COC(=O)C1CCc2n[nH]c(=O)n21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCc2n[nH]c(=O)n21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid methyl ester (0.50 g, 2.7 mmol) was dissolved in THF (3.0 mL). LiOH (0.14 g, 3.3 mmol) was dissolved in water (3.0 mL), which was added to the THF mixture and stirred at room temperature for 30 min. The mixture was acidified with 1N HCl and extracted with DCM. The organic layers were dried over MgSO4, filtered through CELITE®, and concentrated in vacuo to give 3-Oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[OH-].[K+:25]>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[K+:25]
Reactant: Cc1cccc(Cl)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1Cn1nc(C)c2ccc(CC(=O)[O-])cc21

Procedure:
To a solution of the compound [102](33.1 mg) in ethanol (3.0 mL) was added an aqueous solution of 1N-potassium hydroxide (0.1 mL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (35.5 mg) as a white solid.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=3)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[F:56][C:57]1[CH:58]=[C:59]2[C:63](=[CH:64][CH:65]=1)[NH:62][C:61]([C:66]([OH:68])=O)=[CH:60]2>>[F:56][C:57]1[CH:58]=[C:59]2[C:63](=[CH:64][CH:65]=1)[NH:62][C:61]([C:66]([NH:18][C@H:19]([C:44]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=1)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:68])=[CH:60]2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)cc1O
Product: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2cc3cc(F)ccc3[nH]2)cc1O

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-3-hydroxy-4-methoxyaniline (605 mg, 0.8 mmol, example 109, step A) as described for example 109 (step B) using 5-fluoroindole-2-carboxylic acid (222 mg, 1.24 mmol) instead of N-(4-fluorobenzyl)indole-2-carboxylic acid. The crude material was purified by flash chromatography using 10, 20 and 40% EtOAc/CH2Cl2 as the eluent. The title compound was obtained as yellow crystals (400 mg, 72%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.N1C=CC=CC=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>C(Cl)Cl>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
A stirred solution and cooled (20° C.) solution of 2 (5.0 g, 32.89 mmol) in CH2Cl2 (30 mL) was treated with pyridine (5.2 g, 65.82 mmol). After 15 min, Tf2O (11.13 g, 39.4 mmol) was added dropwise and stirred at −20° C. for 1 h. Reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with water (50 mL), brine (50 mL) and dried, Solvent was evaporated under reduced pressure and residue purified by column chromatography (Silica gel, 60-120 mesh, hexane:ethyl acetate 93:7) to give 3 (5.7 g, 61%) as a syrup.
Reaction SMILES: IC.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[OH:14].[C:15](=O)([O-])[O-].[K+].[K+].N>O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:15])[CH:9]=[CH:8][C:7]2=[O:14]
Reactant: Oc1ccnc2ccc(F)cc12
Reactant: O=C([O-])[O-]
Agent: N
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ccc(=O)c2cc(F)ccc21
Reaction time: 18 h

Procedure:
Iodomethane (6.9 ml) was added to a stirred suspension of 6-fluoro-4-hydroxyquinoline (16.3 g) and anhydrous potassium carbonate (15.2 g) in dry tetrahydrofuran (100 ml) at ambient temperature and stirring was continued for 18 hours. More iodomethane (1.8 ml) and anhydrous potassium carbonate (3.8 g) were added and stirring was continued for 4 hours at ambient temperature. Concentrated aqueous ammonia (specific gravity 0.88; 100 ml) was added and the mixture was evaporated to dryness. The residue was treated with water (200 ml) and extracted with dichloromethane (2×400 ml). The extract was dried and evaporated to dryness. The residue was crystallised from ethyl acetate to give the novel compound 6-fluoro-1-methyl-4-quinolone, m.p. 88°-89°.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([C:14]#[C:15][C@:16]2([OH:24])[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[CH:12][CH:11]=[C:10]([N:25]2[CH2:29][C@@H:28]([O:30][CH3:31])[C@H:27]([OH:32])[CH2:26]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[H][H].[Pt](=O)=O>[CH2:1]([C:8]1[C:13]([CH2:14][CH2:15][C@:16]2([OH:24])[CH:21]3[CH2:20][CH2:19][N:18]([CH2:23][CH2:22]3)[CH2:17]2)=[CH:12][CH:11]=[C:10]([N:25]2[CH2:29][C@@H:28]([O:30][CH3:31])[C@H:27]([OH:32])[CH2:26]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: CO[C@@H]1CN(c2ccc(CC[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O

Procedure:
180 mg of the target compound was obtained using 200 mg of (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol (Example 10) in 2 ml of methanol at normal pressure in a hydrogen atmosphere wherein 10 mg of platinum (IV) oxide was used as a catalyst to carry out catalytic reduction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([NH:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:11]=1)=O)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[S:30][C:8]([C:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:11]=2)=[CH:7][N:6]=1)=[O:28]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(=O)NCC(=O)c1cn(CC2CCCCC2)c2c(OC)cccc12
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ncc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)s1
Yield: 98.2 %

Procedure:
To a solution of N-[(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxo-ethyl]-oxalamic acid methyl ester (429 mg, 1.11 mmol) in chloroform (20 ml) was added phosphorus pentasulfide (538 mg, 1.21 mmol) and the reaction mixture heated at reflux for 3.5 h. The reaction mixture was cooled, poured into a separating funnel and washed with water and then brine. The organic layers were then dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting solid was purified by flash column chromatography eluting with dichloromethane to give 5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazole-2-carboxylic acid methyl ester (418 mg, 1.09 mmol) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH3:2].CN(C)C(=N)N(C)C.[N+:24]([CH3:27])([O-:26])=[O:25]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH2:27][N+:24]([O-:26])=[O:25])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=Cc1ccc(OC)cc1
Agent: CN(C)C(=N)N(C)C
Product: CCOC(=O)CC(C[N+](=O)[O-])c1ccc(OC)cc1

Procedure:
A solution of 3-(4-methoxy-phenyl)acrylic acid ethyl ester (1.0 g) and tetramethyl-guanidine (125 μL) was stirred for 24 h at 70° C. in 2.5 mL nitromethane. The solvent was evaporated and the resulting residue was partitioned in 50 mL 1 N hydrochloric acid and 50 mL ethyl ether. The ethyl ether phase was collected and washed with 50 mL 1 N hydrochloric acid. The ether phase was dried over sodium sulfate and the solvent was evaporated to furnish 1.15 g of 3-(4-methoxyphenyl)-4-nitrobutyric acid ethyl ester.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=O)[CH:21]=[N:22][CH:23]=1.O>C1COCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH:21]=[N:22][CH:23]=1
Reactant: COc1cncc(C=O)c1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cncc(OC)c1
Temperature: 0 °C
Yield: 13.9 %

Procedure:
To a suspension of 3.12 g (78.1 mmol) of sodium hydride (60% in oil) in 30 mL of anhydrous THF is added, over 45 minutes, under argon and at 0° C., 16.4 g (78.1 mmol) of methyl (diethoxyphosphoryl)acetate in 10 mL of THF. Stirring is maintained for 30 minutes at 0° C. and 5.1 g (37.2 mmol) of 5-methoxypyridine-3-carbaldehyde in 20 mL of anhydrous THF are then added dropwise at 0° C. After cooling to room temperature, the reaction mixture is treated with 150 mL of water and then extracted with EtOAc (3×100 mL). The organic phases are combined, washed successively with water (2×20 mL), dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAC gradient of 0 to 40% EtOAc. 1 g of methyl (2E)-3-(5-methoxypyridin-3-yl)prop-2-enoate is obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[N:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH2:40])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: Nc1ccccc1N1CCCCC1
Product: O=C(Nc1ccccc1N1CCCCC1)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 2-piperidin-1-yl-phenylamine (commercially available; CAS RN 39643-31-7). White foam (90%). MS (ESI): 442.108 [M+H]+.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.OC1CC[NH:32]CC1>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:32]
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: OC1CCNCC1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 196.5 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.300 g, 0.770 mmol, 1 eq, Example 56, Step D) was suspended in Dioxane (20 mL) under Ar. 4-Hydroxypiperidine (0.234 g, 2.320 mmol, 3 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.200 g (66%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 393 (M+1); Anal. Calcd for C24H28N2O3.1HCl.0.4H2O: C, 66.09; H, 6.89; N, 6.42; Found: C, 66.18; H, 6.77; N, 6.30.
Reaction SMILES: [F:1][CH:2]([F:40])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C1C=C(C([O-])=[O:48])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[F:40][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N+:19]([O-:48])=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: FC(F)Oc1ccc(C(Cc2ccncc2)c2ccc(Oc3ccc(OC(F)(F)F)cc3)nc2)cc1OC(F)F
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: [O-][n+]1ccc(CC(c2ccc(Oc3ccc(OC(F)(F)F)cc3)nc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 162 %

Procedure:
To a solution of 4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-{6-[4-(trifluoromethoxy)phenoxy]-3-pyridyl}ethyl}pyridine (340 mg, 0.598 mmol) from Step 5 above in a mixture of 6 mL of CH2Cl2 and 0.6 mL of MeOH, was added MMPP (222 mg, 0.359 mmol) in one portion. The mixture was stirred 24 h at room temperature and the reaction was completed with an other 50 mg of MMPP. The reaction was quenched with a saturated aqueous NaHCO3 solution and diluted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5% MeOH/CH2Cl2) to afford the title compound as an amorphous solid (340 mg, 97%).