Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1>C(O)(C)C>[CH2:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[CH:6][N:5]=2)[CH2:29][CH2:28]1)=[O:31])[CH3:34]
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CC(C)O
Product: CCOC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1
Yield: 85.1 %

Procedure:
A suspension of (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone (20.0 mg, 0.0650 mmol, Example 6) and ethyl 4-amino-1-piperidinecarboxylate (15.1 mg, 0.0876 mmol, Aldrich) in isopropanol (2.5 mL) was placed in a sealed tube and heated at ˜100–110° C. under microwave conditions for ˜1 hour and the resulting mixture was evaporated in vacuo. The crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid ethyl ester as a light yellow solid (22.1 mg, 89% yield). HRMS, observed: 400.1984; Calcd for (M+H)+: 400.1980.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:15]=1[C:16]([NH:18][CH3:19])=[O:17].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:15]=2[C:16]([NH:18][CH3:19])=[O:17])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: CNC(=O)c1c(N)cccc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1c(Nc2cc(Cl)ncc2C(F)(F)F)cccc1OC
Temperature: 90 °C
Reaction time: 15 h
Yield: 65.9 %

Procedure:
2-Chloro-4-iodo-5-(trifluoromethyl)pyridine (420 mg, 1.37 mmol), 2-amino-6-methoxy-N-methylbenzamide (246 mg, 1.37 mmol), palladium(II) acetate (24.54 mg, 0.11 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (126 mg, 0.22 mmol) and cesium carbonate (534 mg, 1.64 mmol) were mixed together in dioxane (8 mL). Reaction was degassed with argon and was stirred at 90° C. overnight (15 hours) under argon. The reaction mixture was filtered, washed with DCM and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10 to 30% EtOAc in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (325 mg, 66%) as a white solid. 1H NMR spectrum (500 MHz, DMSO): 2.68 (d, 3H), 3.83 (s, 3H), 6.84 (s, 1H), 7.03 (d, 1H), 7.08 (d, 1H), 7.47 (dd, 1H), 8.19 (q, 1H), 8.42 (s, 1H), 9.15 (s, 1H); Mass spectrum: ESI+ MH+ 360.
Reaction SMILES: C1(S[CH:8]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9]([OH:11])=[O:10])C=CC=CC=1>C(O)(=O)C.[Zn]>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(Sc1ccccc1)c1cccs1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)Cc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
α-Phenylthio-2-thiopheneacetic acid (890 mg, 3.56 mmol) was dissolved in acetic acid (6 ml), then zinc dust (350 mg, 5.4 mmol) was added and the mixture was heated under reflux with vigorous stirring. After 30 min., zinc dust (350 mg, 5.4 mmol) was added again, and the mixture was heated under reflux for another 4 hr. with stirring, then cooled to room temperature, and most of the solvent was removed by distillation. Water and ethyl acetate were added and the precipitate was filtered off by the use of celite, and the layers of the filtrate were separated. The organic layer was washed with an aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After filtration, the solution was concentrated under a reduced pressure and the crystals thus obtained were further recrystallized from ethyl acetate: n-hexane to give 2-thiopheneacetic acid (430 mg) melting at 62° C. (literature value: 62°-65° C.).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])(=O)=O>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: OCc1ccccc1CBr
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CBr
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 88.1 %

Procedure:
To a solution of the title compound of step (A) (10 g, 50 mmol) in CH2Cl2 (80 ml) cooled at 0° C. was added 2,6-lutidine (7.57 mL, 65 mmol), followed by dropwise addition of tert-butyldimethylsilyl trifluoromethanesulfonate (14.92 mL, 65 mmol). The reaction mixture was stirred at 0° C. for 45 minutes, then quenched with H2O (20 mL) and partitioned between EtOAc (450 mL) and H2O (150 mL). The organic layer was separated and washed with 10% NaHCO3 solution, brine (2×), dried (MgSO4) and concentrated in vacuo to give a yellow syrup, which was chromatographed eluting with 10-50% EtOAc/hexane to afford 13.89 g (88%) of the title compound of this step as a light yellow oil.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32]([O:38][CH3:39])[N:31]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32]([O:38][CH3:39])[N:31]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Product: COc1cc(-c2ccc3c(c2)ncn3-c2ccnc(N[C@@H](C)c3ccccc3)n2)nc(OC)n1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 4-chloro-2,6-dimethoxypyrimidine. Mass spectrum (ESI) 443.4 (M+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].C(N(C(C)C)C(C)C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:5]([S:2]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:4])=[O:3])[CH:6]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (1.0 g, 3.3 mmol, Buttpark Ltd.) in dichloromethane (10 mL) was added N-ethyldiisopropylamine (854 mg, 1.15 mL, 6.61 mmol) and morpholine (317 mg, 317 μL, 3.63 mmol). The reaction mixture was stirred at room temperature for 2 hours, poured on 10% aqueous sodium bicarbonate solution (100 mL) and dichloromethane (100 mL) and the layers were separated. The aqueous layer was extracted a second time with dichloromethane (100 mL). The organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 35:65). Off-white solid (1.04 g, 89%). MS (EI): m/z=353.087 ([M]).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:48]([OH:50])=O)[CH2:46][OH:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:51]([O:55][C:56](=[O:63])[NH:57][CH2:58][CH:59]([OH:62])[CH2:60][NH2:61])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@@H:45]([CH2:46][OH:47])[C:48]([NH:61][CH2:60][CH:59]([OH:62])[CH2:58][NH:57][C:56]([O:55][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:63])=[O:50])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
362.8 mg (0.954 mmol) of HATU and 123.3 mg (0.954 mmol) of N,N-diisopropylethylamine are added to a solution of 207.5 mg (0.867 mmol) of N-[(benzyloxy)carbonyl]-L-serine in 10 ml of anhydrous DMF. After stirring at RT for 15 min, 165 mg (0.867 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1.[CH2:27]([O:29][C:30](=[O:41])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=1[CH3:40])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.O.[Cu]Cl>[CH2:27]([O:29][C:30](=[O:41])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:26][C:4]2[CH:5]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][C:10]=3[O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:35][C:34]=1[CH3:40])[CH3:28]
Reactant: Cc1cc(O)cc(Oc2ccc(C(F)(F)F)cc2Oc2ccccc2)c1
Reactant: CCOC(=O)COc1ccc(Br)cc1C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)COc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)cc1C
Temperature: 120 °C
Yield: 12.5 %

Procedure:
Intermediates 3-methyl-5-(2-phenoxy-4-trifluoromethyl-phenoxy)-phenol (0.49 g, 1.36 mmol) and (4-bromo-2-methyl-phenoxy)-acetic acid ethyl ester (0.37 g, 1.36 mol) were combined with cesium carbonate (0.53 g, 1.63 mol), and 2,2,6,6-tetramethyl-3,5-heptanedione (0.063 g, 0.342 mmol) in 1-methyl-2-pyrrolidinone (10 mL) is purged with N2, and then copper (I) chloride (0.067 g, 0.677 mmol) is added. The reaction mixture is heated to 120° C. for 20 hours under N2. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 0.094 g (13%) {2-methyl-4-[3-methyl-5-(2-phenoxy-4-trifluoromethyl-phenoxy)-phenoxy]-phenoxy}-acetic acid ethyl ester that was saponified with ethanol and 5 N NaOH to afford 0.072 g (81%) 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H23O6F3 524, found 525 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH2:3][OH:4].CCN(CC)CC.[Br:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Br)=[O:21])=[CH:18][CH:17]=1.O>C(Cl)Cl>[Cl:1][C:2]([Cl:6])([Cl:5])[CH2:3][O:4][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH2:15][Br:14])=[CH:17][CH:18]=1
Reactant: O=C(Br)c1ccc(CBr)cc1
Reactant: OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,2,2-trichloroethanol (2.46 g, 16.5 mmol) and NEt3 (1.67 g, 16.5 mmol) in CH2Cl2 (40 ml) at 0° C. was dropwise added 4-bromomethyl benzoylbromide (4.17 g, 15.0 mmol) in CH2Cl2 (20 ml) and stirred to room temperature overnight. The reaction mixture was added H2O (20 ml) and the organic layer separated. The organic layer washed with aqueous 1 M HCl (20 ml) and H2O (20 ml). The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo to leave the expected product as a white solid. The product was used directly in the next step without any further purification (to be filled in).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([NH2:16])=[O:15].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][CH:26]([C:29](OCC)=O)[CH2:25][CH2:24]2)[CH:18]=1>C(O)C>[CH3:13][C:4]1[C:3]2[C:14](=[O:15])[NH:16][C:29]([CH:26]3[CH2:25][CH2:24][N:23]([C:19]4[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=4)[CH2:28][CH2:27]3)=[N:1][C:2]=2[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1
Reactant: Cc1nn(-c2ccccc2)c(N)c1C(N)=O
Reactant: CCOC(=O)C1CCN(c2cccnc2)CC1
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c2nc(C3CCN(c4cccnc4)CC3)[nH]c(=O)c12

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of Na (64 mg, 2.78 mmol, 6.00 equiv) in ethanol (5 mL) at room temperature. To the resulting mixture was then added a solution of 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (100 mg, 0.46 mmol, 1.00 equiv) in C4H10O (10 mL), in portions at room temperature, followed by a solution of ethyl 1-(pyridin-3-yl)piperidine-4-carboxylate (650 mg, 2.78 mmol, 6.00 equiv) in C4H10O (20 mL), in portions at room temperature. The resulting solution was heated to reflux for 5 hr. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with DCM (3×30 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride (2×50 mL), then dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1) to yield 3-methyl-1-phenyl-6-(1-(pyridin-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one as a white solid.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:9]=1.O>CO>[C:1]([O:4][CH2:13][C:12]([C:11]1[CH:16]=[CH:17][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)=[O:15])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)COC(C)=O)cc1
Yield: 64.5 %

Procedure:
To a solution of 63 g potassium acetate in 750 ml of methanol, 92.9 g of 4-methoxyphenacyl bromide was dropped in. The resulting solution was refluxed for 4 hours, then cooled and poured into water. The aqueous layer was extracted with ether, then the combined organic phases were washed with water, dried, and evaporated to dryness. The resulting solid was recrystallized from methanol to yield 54.5 g crystals.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:94]=[C:95]([F:97])[CH:96]=1)[CH2:50][N:51]1[CH:55]=[CH:54][C:53]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:97][C:95]1[CH:94]=[C:49]([CH:48]=[C:47]([F:46])[CH:96]=1)[CH2:50][N:51]1[CH:55]=[CH:54][C:53]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:75][CH2:76]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5ccn(Cc6cc(F)cc(F)c6)n5)c4c3)cc2)CC1
Yield: 34.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (55 mg, 0.0759 mmol) was hydrolyzed by lithium hydroxide (10 mg, 0.227 mmol) in THF/methanol/water (2/2/1 ml) to yield 15 mg (34.6% yield) of the titled compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6](=[CH:9][C:10](OCC)=[O:11])[CH2:5][CH2:4]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[OH:11][CH2:10][CH:9]=[C:6]1[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: CCOC(=O)C=C1CCC(C#N)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1CCC(=CCO)CC1
Reaction time: 2 h

Procedure:
To the stirred solution of crude ethyl 2-(4-cyanocyclohexylidene)acetate in THF (12 mL) was added LAH (187 mg, 4.91 mmol) at 10° C. The reaction mixture was allowed to stir at the same temperature for 2 h, water (1.2 mL), aqueous 15% NaOH (1.2 mL), and water (4.0 mL) were each carefully added to the mixture. The resulting slurry was filtered through a pad of Celite and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the desired product as a mixture of isomers. (216 mg, 1.43 mmol, 32%). 1H NMR: 0.94-1.02 (m, 1H), 1.31-1.41 (m, 5H), 1.46-1.61 (m, 9H), 1.73-2.00 (m, 11H), 2.09-2.23 (m, 3H), 2.34-2.48 (m, 3H), 2.78-2.82 (m, 1H), 2.92-2.94 (m, 1H), 3.67-3.72 (m, 3H), 4.15 (d, 2H, J=6.8 Hz), 5.45 (t, 1H, J=6.8 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=[O:2].O.Cl>CO.[OH-].[Na+]>[CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=[O:2]
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1C=O
Reaction time: 1 h
Yield: 93.4 %

Procedure:
1.72 g of methyl 4-formyl-3-methoxybenzoate was dissolved in 8.6 mL of methanol, to which 2.6 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and this solution was stirred for one hour at the same temperature. The reaction mixture, to which water was added, was adjusted to pH 2 with 6M hydrochloric acid, and resultant precipitate was filtered out therefrom and washed with water to yield 1.49 g of 4-formyl-3-methoxybenzoic acid as light yellow solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[OH-].[Na+].[CH2:12]([CH:14]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH3:13]>O.C(O)C>[CH2:12]([CH:14]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[C:2]2[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][N:1]2[CH2:6][CH2:5]3)=[CH:23][CH:24]=1)[CH3:13]
Reactant: CCCCC(CC)COc1ccc(C=O)cc1
Reactant: O=C1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCC(CC)COc1ccc(C=C2C(=O)C3CCN2CC3)cc1

Procedure:
A solution of 16.0 g of 3-quinuclidinone (hydrochloride) in 100 ml of water is treated with 100 ml of a 32% sodium hydroxide solution. 36.0 g of 4-(2-ethylhexyloxy)benzaldehyde [can be prepared from p-hydroxybenzaldehyde by reaction with 1-chloro-2-ethylhexane], dissolved in 250 ml of ethanol, is then added with stirring and the mixture is heated under reflux for 3 hours. After the reaction is complete, it is worked up in the customary manner. 2-[4-(2-ethylhexyloxy)benzylidene]quinuclidin-3-one is obtained in the form of a pale yellow solid; m.p. 37°, λmax =331 nm, E=0.8.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][CH2:15][C:14]3=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B1C2CCCC1CCC2>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][CH2:16][C@@H:17]3[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)=[CH:9][CH:8]=2)=[CH:29][CH:30]=1
Reactant: O=C1CC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc([C@H]2CCCN2c2ccc(Oc3ccc(Cl)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of (R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (6.4 mg, 0.015 mmol), THF (0.5 mL) and 9-BBN (0.5 M in hexane, 0.5 mL) is stirred at room temperature overnight. After concentration, the residue is purified on silica gel (0-30% ethyl acetate in hexane) to give the title compound (5.1 mg, 82%) as a colorless oil. HPLC-MS calculated for C23H19ClF3NO (M+H+) 418.11, found 418.10.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:16][C:17]1[N+:22]([O-:6])=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1ccc(Cl)nc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Cl)[n+]([O-])c1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Hydrogen peroxide (0.409 mL of a 30% aqueous solution, 3.6 mmol) was added slowly to a stirred solution of trifluoroacetic anhydride (0.915 mL, 6.55 mmol) in DCM (5 mL) with heating under reflux. After 30 min, methyl (6-chloropyridin-3-yl)acetate (Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (2004), 43B(4), 864) (608 mg, 3.28 mmol) was added as a solution in DCM (5 mL). The reaction mixture was stirred under reflux for 1 h and then allowed to cool with stirring for 16 h. Solid potassium carbonate was added until there was no more effervescence then the mixture was filtered, concentrated by evaporation and the resultant oil was triturated with Et2O to give the title compound (291 mg, 44%) as a solid; 1H NMR δ 3.64 (s, 3H), 3.79 (s, 2H), 7.30 (d, 1H), 7.75 (d, 1H), 8.45 (s, 1H); MS m/e MH+ 202.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].[BH4-].[Na+].Cl>C1C=CC=CC=1.CO.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.O>[CH2:13]([N:16]([CH2:17][CH2:18][CH3:19])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: O=C1CCc2cccc(Cl)c2C1
Reactant: CCCNCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
To a solution of 8-chloro-2-tetralone (3.0 gm, 16.6 mMol) in benzene (25 mL) were added dipropylamine (3.35 mL, 33.2 mMol) and p-toluenesulfonic acid (100 mg), and the reaction mixture was heated at reflux for 4 hours with constant water removal (Dean-Stark trap). The reaction mixture was then cooled to room temperature, and the volatiles were removed in vacuo to give a dark viscous residue. To a solution of this crude material in methanol (30 mL) were added acetic acid (3 mL) followed by the dropwise addition of sodium borohydride (1.5 gm) in ethanol (60 mL) with cooling. The reaction mixture was stirred for 18 hours at room temperature. To this was then added hydrochloric acid (6M, 20 mL) and the mixture stirred 4 hours at room temperature. The volatiles were then removed in vacuo and the residue triturated with water. The aqueous phase was extracted once with diethyl ether, and the organic phase was discarded. The remaining aqueous phase was made basic with concentrated ammonium hydroxide and was then extracted well with dichloromethane. The organic extracts were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo to give an orange liquid. Purification by chromatography on basic alumina (Activity I, dichloromethane) gave a colorless liquid (1.75 gm, 40%). The hydrochloride salt was formed and recrystallized (ethanol/diethyl ether) to give a colorless, crystalline-solid (m.p.=159°-160° C.).