Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=O)[N:3]=1.[CH3:21][NH:22][C:23](=[O:30])[C@H:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[NH2:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C:5]2=[C:4]([C:18](=[O:20])[NH:25][C@@H:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([NH:22][CH3:21])=[O:30])[N:3]=1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
Acid Intermediate 1I (0.62 g, 1.79 mmol) was dissolved in DMF and L-tert-Leucine methylamide (0.31 g, 2.14 mmol) was added followed by DIEA (0.94 mL, 5.37 mmol). The resulting mixture was stirred for 20 minutes, HBTU (0.75 g, 1.97 mmol) was added in one portion and the mixture was stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, then brine, and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by normal phase chromatography, eluting with a 0-10% methanol/DCM gradient to provide product Intermediate 1J as an off-white solid (0.68 g, 80%).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[O:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:10][C:7]2=[N:8][CH:9]=1.C=O.[C:20]([O-])([O-])=O.[K+].[K+]>C(O)=O>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]2[O:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH3:20])=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: Clc1cnc2cc([C@@H]3CCCN3)oc2c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O=CO
Product: CN1CCC[C@H]1c1cc2ncc(Cl)cc2o1

Procedure:
A 315 mg (1.04 mmol) sample of 6-chloro-2-(2-(S)-pyrrolidinyl)-furo[3,2-b]pyridine dihydrochloride, from Example 7c above, was dissolved in 3 mL of 88% formic acid and 6 mL of 37% aqueous formaldehyde and heated at reflux for 0.5 hour. The reaction mixture was cooled, poured into saturated K2CO3, and the mixture was extracted with CH2Cl2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :MeOH. The residue was converted to the salt by treatment with HCl/ether, and the salt was recrystallized from ethanol/EtOAc to give 159 mg of title compound: 1H NMR (D2O, 300 MHz) δ 2.31-2.39 (m, 2H), 2.52-2.70 (m, 3H), 2.96 (br s, 3H), 3.55 (br s, 1H), 3.88 (br s, 1H), 7.33 (s, 1H), 8.13 (dd, 1H), 8.56 (d, 1H); MS m/z: 237 (M+H)+, 254 (M+NH4)+ ; Anal. Calcd for C12H13N2OCl.2HCl: C, 46.55; H, 4.88; N, 9.05. Found: C, 50.75; H, 5.12; N, 9.69.
Reaction SMILES: [F:1]/[C:2](/[CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH3:14])[CH2:8][CH2:7]1)=[C:3](/[F:5])\I.[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH3:25])[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.C1(C)C=CC=CC=1>[F:5]/[C:3](/[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH3:25])=[C:21]([F:22])[C:16]=1[F:15])=[C:2](/[F:1])\[CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH3:14])[CH2:8][CH2:7]1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: CCCC1CCC(/C(F)=C(\F)I)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCC1CCC(/C(F)=C(\F)c2ccc(OCC)c(F)c2F)CC1

Procedure:
6.30 g (20.1 mmol) of 1-((Z)-1,2-difluoro-2-iodovinyl)-4-propylcyclohexane and 4.86 g (24.1 mmol) of 2,3-difluoro-4-ethoxybenzeneboronic acid are refluxed for 19 h together with 1.16 g (1.0 mmol) of tetrakistriphenylpalladium(0) and 20 ml (20 mmol) of sodium carbonate solution (2 M) in 90 ml of ethanol/toluene (2:1). Water is added, and the batch is extracted with MTBE. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=4:1). The further purification is carried out by recrystallisation from n-heptane, giving 1-[(E)-1,2-difluoro-2-(4-propylcyclohexyl)vinyl]-4-ethoxy-2,3-difluorobenzene as a colourless solid (m.p. 60° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:72](=O)([O-:74])[O-:73].[K+].[K+].O>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[F:29])[C:72]([OH:74])=[O:73])([CH2:27][F:28])[N:9]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Temperature: 90 °C
Yield: 21.7 %

Procedure:
To a mixture of N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (2.19 g, 4.59 mmol), bis(tri-t-butylphosphine)palladium(0) (0.23 g, 0.46 mmol), xantphos (0.53 g, 0.92 mmol), potassium carbonate (1.90 g, 13.76 mmol) in DMF (15 mL) and water (0.83 ml, 45.9 mmol) was bubbled CO gas for 10 min. The mixture was heated at 90° C. for 4 h, then was allowed to cool to rt. 1N HCl was added until pH˜4. Water was then added and a precipitate was formed. The solid was filtered, washed with water, and dried. The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatographed, eluting with a gradient of 1% to 8% MeOH in 0.5% AcOH/DCM, to provide the acid as a white solid (0.44 g, 21.45% yield). MS m/z=443 [M+H]+. Calculated for C20H15F5N2O4: 442.3.
Reaction SMILES: [Br-].O1CCCOC1CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[CH2:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][C:55]3=O)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)[CH2:40][CH3:41]>CCOCC>[CH2:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[CH:50][C:51]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:52][CH:53]=2)=[CH:44][CH:43]=1)[CH2:40][CH3:41]
Reactant: CCCc1ccc(-c2ccc(C3CCCCC3=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1ccc(-c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (22.9 g, 50 mmols), followed by adding tetrahydrofuran (100 ml), suspending, stirring the suspension under ice cooling till the liquid temperature reached 10° C. The resulting reaction mixture is added pottasium t-butoxide (5.6 g, 50 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (100ml) solution of (4-(4-propylphenyl)phenyl)cyclohexanone (14.0 g, 48 mmols) over 30 minutes from the dropping funnel, further stirring the reaction liquid for 5 hours after completion of the dropwise addition, adding ether (200 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduce pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(2,3-dioxan-2-yl)ethylidene)-4-(4-(4-propylphenyl)-phenylcyclohexane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:28]1([C:34]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45]3[C:36](=[C:37]4[C:42](=[CH:43][CH:44]=3)[C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:40][CH:39]=[N:38]4)[N:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C1COCC1>[C:28]1([C:34]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45]3[C:36](=[C:37]4[C:42](=[CH:43][CH:44]=3)[C:41]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:40][C:39]([C:2]3[CH:7]=[CH:6][C:5]([C:8]5[N:12]([C:13]6[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:11]6[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=6[N:9]=5)=[CH:4][CH:3]=3)=[N:38]4)[N:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)ccnc4c3n2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)cc(-c5ccc(-c6nc7ccccc7n6-c6ccccc6)cc5)nc4c3n2)cc1
Temperature: -78 °C
Yield: 47 %

Procedure:
To a three-necked flask of 250 ml, 3.84 g (11 mmol) of 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazole and 70 ml of THF were charged, then 6.9 ml (11 mmol) n-butyllithium (1.6M in Hexane solution) was dropped under stirring at −78° C. in a nitrogen atmosphere. The mixture was stirred for one hour at −78° C., and a solution of 2.29 g (5.6 mmol) 2,4,7-triphenyl-1,10-phenanthroline in 30 ml THF was dropped. Then the mixture was stirred at room temperature for overnight and was added with water. The organic layer was extracted with Dichloromethane and dried with anhydrous magnesium sulfate, the solvent was removed by rotary evaporation. The product was purified by column chromatography on alumina using Dichloromethane/Hexane as eluent and dried in vacuo, obtaining white powder compound 1.78 g (yield of 47.12%). MS (m/z, FAB+) 676.8(100%).
Reaction SMILES: [H][H].[CH3:3][C:4]([NH:7][CH2:8][CH:9]([OH:19])[C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH2:16][OH:17])[CH:15]=1)([CH3:6])[CH3:5].[ClH:20].CCOCC>C(O)C.[Pd].C(OC)(C)(C)C>[CH3:6][C:4]([NH:7][CH2:8][C@H:9]([OH:19])[C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH2:16][OH:17])[CH:15]=1)([CH3:3])[CH3:5].[ClH:20]
Reactant: [H][H]
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(CO)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)(C)C
Solvent: CCO
Product: CC(C)(C)NC[C@H](O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of (R)-4-benzyl albuterol from Example-3 (6.6 g, 20 mmol) and 10% Pd/C (1.32 g) in 50 mL of ethanol (denatured with 5 vol % 2-propanol) is shaken on a Parr-hydrogenator under 50 psi of hydrogen at room temperature for 2-3 hours. The catalyst is removed by filtration and the filtrate is concentrated to give crude (R)-albuterol (compound IIIa). The crude albuterol (20 mmol) is dissolved in 20 mL of ethanol and treated with anhydrous HCl in ether (1.0M, 19 mL, 0.95 eq) at 0°-5° C. After 30 min at room temperature, 20 mL of methyl t-butyl ether (MTBE) is added to the mixture and the resulting mixture is stirred at room temperature for 30 min and at 0°-5° C. for 2 hours. The white solid (R)-albuterol hydrochloride (compound IIIb) is collected by filtration and recrystallized from 52 mL of ethanol and 26 mL of MTBE to give pure (R)-albuterol hydrochloride as a white powder (4.6 g, 83.5% yield, 99.6% ee, 99.3% purity).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH2:4][O:5][C:6]1[C:15]([CH3:16])=[C:14]2[C:9]([C:10](O)=[CH:11][C:12]([C:17]3[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=3)=[N:13]2)=[CH:8][CH:7]=1.O=P(Cl)(Cl)[Cl:30].CO.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:30][C:10]1[C:9]2[C:14](=[C:15]([CH3:16])[C:6]([O:5][CH2:4][CH:3]([O:26][CH3:27])[O:2][CH3:1])=[CH:7][CH:8]=2)[N:13]=[C:12]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COC(COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1C)OC
Temperature: 80 °C

Procedure:
7-(2,2-Dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-8-methyl-quinolin-4-ol (875 mg, 2.3 mmol) was dissolved in pyridine (20 mL). POCl3 (4.2 ml, 46.0 mmol) was added slowly. The reaction was heated at 80° C. for 4 hours. The reaction was cooled to 0° C. and methanol (5 mL) was added. The reaction was neutralized with a saturated aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate (3×20 mL). The combined organics were dried with sodium sulfate, filtered and was concentrated. 4-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-8-methyl-quinoline (410 mg, 44%) was purified by silica gel chromatography.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:6]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@H:13]([B:19]1[O:23][C@@H]2C[C@@H]3C[C@H]([C@]2(C)[O:20]1)C3(C)C)[CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1)=[O:11])=[O:7])(=[O:3])[CH3:2].CO.CCCCCC.Cl.CC(C)CB(O)O>>[C:1]([NH:4][C@@H:5]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:6]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:10]([NH:12][C@H:13]([B:19]([OH:23])[OH:20])[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18]1)=[O:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC1CCC1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CC(C)CB(O)O
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Product: CC(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC1CCC1)B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
Into a 1-neck round-bottom flask was added (2S)-2-(acetylamino)-N-[(1S)-1-benzyl-2-({(1R)-2-cyclobutyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}amino)-2-oxoethyl]-4-phenylbutanamide (24.8 mg, 0.0395 mmol), methanol (0.237 mL, 5.86 mmol), hexane (0.237 mL, 1.81 mmol), hydrochloric acid (0.0889 mmol, 0.0889 mmol) and 2-methylpropylboronic acid (8.65 mg, 0.0849 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative TLC in 10% MeOH/CH2Cl2 to give 9.90 mg (51% yield) of desired product as a white solid. 1H NMR (CD3OD, 300 MHz, δ): 7.32-7.12 (m, 10H); 4.74 (t, J=7.94 Hz, 1H); 4.26 (dd, J=5.49, 8.55 Hz, 1H); 3.14-3.05 (m, 2H); 2.66-2.55 (m, 2H); 2.48-2.41 (m, 1H); 2.19-2.05 (m, 1H); 2.04-1.89 (m, 8H); 1.89-1.69 (m, 3H); 1.58-1.36 (m, 3H); 1.33-1.22 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[NH2:13][C:14]([NH2:16])=[S:15].II>C(O)C.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1[N:13]=[C:14]([NH2:16])[S:15][C:7]=1[CH2:6][CH2:5]2
Reactant: NC(N)=S
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc2c(s1)CCc1cc(Br)ccc1-2
Temperature: 100 °C
Yield: 99.9 %

Procedure:
6-bromo-3,4-dihydronaphthalen-1(2H)-one (3.5 g, 15.55 mmol), thiourea (3.55 g, 46.6 mmol) and iodine (4.34 g, 17.10 mmol) were dissolved in 20 ml of ethanol and the solution was heated at 100° C. for 4 hr. The volume of ethanol was reduced and the solid amine hydroiodide salt was filtered and washed with ether. The solid obtained was dissolved in water and basified with 10% NaOH solution and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated to obtain the desired compound (4a) (4.37 g, 80%). m/z 280.9 (79Br) & 282.9 (81Br) (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([C:32]5[S:33][CH:34]=[CH:35][N:36]=5)=[O:31])[CH2:26][CH2:25]4)[CH2:21]3)=[O:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[S:33]1[CH:34]=[CH:35][N:36]=[C:32]1[C:30]([N:27]1[CH2:28][CH2:29][N:24]([CH:22]2[CH2:23][N:20]([C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][NH:8][CH2:17][CH2:16]4)=[O:19])[CH2:21]2)[CH2:25][CH2:26]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)N3CC(N4CCN(C(=O)c5nccs5)CC4)C3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)CCNC2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.9 %

Procedure:
To a solution of compound 17c (826 mg, 1.61 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was extracted with CH2Cl2, and H2O after basifying the water layer to pH˜8 with 1N aqueous NaOH. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 916 (675 mg). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=3.3 Hz, 1H), 7.55 (d, J=3.3 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=8.03 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 4.54 (br. s., 1H), 4.44 (br. s., 1H), 4.01-4.35 (m, 6H), 3.75-3.95 (m, 2H), 3.12-3.31 (m, 2H), 2.85 (t, J=5.8 Hz, 1H), 2.49 (br. s., 4H). MS m/z (M+H+) 412.0.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=1>>[F:23][CH2:22][C:18]1[N:17]=[C:16]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[C:13](=[O:14])[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6]2)[CH:21]=[CH:20][CH:19]=1
Reactant: C#CCCn1nc2ccccn2c1=O
Reactant: FCc1cccc(Br)n1
Product: O=c1n(CCC#Cc2cccc(CF)n2)nc2ccccn12
Yield: 18.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (70 mg, 0.37 mmol, Example 39(A)) and 2-bromo-6-(fluoromethyl)pyridine (78 mg, 0.41 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 20 mg (67 μmol, 18%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as an orange solid (M.P.=106-107° C.).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CO>C1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[O:13][CH3:14])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: COc1cc(F)ccc1C(=O)N1CC1
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(F)ccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 8 parts of 1-(4-fluoro-2-methoxybenzoyl)-aziridine, 3.7 parts of 4-(4-chlorophenyl)-4-piperidinol, 54 parts of benzene and 8 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled to room temperature and 90 parts of benzene are added. The whole is washed with water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 3.5 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-4-fluoro-2-methoxybenzamide; mp. 156.7° C.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[NH2:42][C:43]1[C:47](C#N)=[C:46]([C:50]#[N:51])[NH:45][N:44]=1>>[C:43]([C:47]1[C:46]([C:50]#[N:51])=[N:45][N:44]2[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:17]=12)#[N:42]
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1[nH]nc(N)c1C#N
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: N#Cc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 4.86 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 50 ml. of glacial acetic and 2.66 g. of 3-aminopyrazole-4,5-dicarbonitrile is refluxed for 10 hours and the solvent removed under reduced pressure. The residue is reacted with trifluoroacetic anhydride to give the product of the example.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:20]=[C:19]([CH3:21])[C:14]([C:15]([O:17]C)=[O:16])=[C:13](/[CH:22]=[CH:23]/[CH3:24])[N:12]=1)[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:12]=[C:13]2[CH2:22][CH:23]([CH3:24])[O:17][C:15](=[O:16])[C:14]2=[C:19]([CH3:21])[CH:20]=1)[CH3:10]
Reactant: C/C=C/c1nc(-c2c(CC)cccc2CC)cc(C)c1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(CC)c1-c1cc(C)c2c(n1)CC(C)OC2=O
Temperature: 160 °C
Reaction time: 0.75 h

Procedure:
A mixture of (E)-methyl 6-(2,6-diethylphenyl)-4-methyl-2-(prop-1-enyl)nicotinate (150 mg, 0.464 mmol), H2O (0.17 mL, 9.28 mmol) and TFA (2.9 mL, 37.1 mmol) was heated in a microwave reactor at 160° C. for 30 min. Starting materal was observed. Additional TFA (0.5 mL) and H2O (0.05 mL) were added and heating continued at 160° C. for 45 min and then at 140° C. for 2 h. The reaction was then poured into sat NaHCO3 and extracted with EtOAc. The organic layer was washed with brine and then dried over Na2SO4 and concentrated. The residue was then purified with FCC (0-50% EtOAc/heptane) to provide 2-(2,6-diethylphenyl)-4,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one. MS (ESI+) m/z 310.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].CO>O1CCCC1>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])(=[O:14])[CH3:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
2-Amino-4-nitrophenol (10 g, 0.065 mol) was dissolved in tetrahydrofuran (100 ml) and, after cooling to 0° C., acetic anhydride (12.24 ml, 0.130 mol) was added dropwise, followed by stirring at room temperature for 2 h. Thereafter, methanol (10 ml) was added to the reaction mixture, which was then stirred at room temperature for 30 min and, thereafter, the solvent was evaporated and the resulting residue was diluted with diethyl ether and filtered. The solvent was evaporated off the filtrate and the resulting solids were dried to yield the end compound 2-acetamido-4-nitrophenol (12.21 g) as a pale brown solid mass.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:13][C:14]#[N:15]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]#[N:15])[CH2:8][CH2:7]1
Reactant: COCCOC1CCNCC1
Reactant: N#CCBr
Product: COCCOC1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 4-(2-Methoxy-ethoxy)-piperidine (commercially available from ChemBridge Corporation) and bromoacetonitrile analogously to the preparation of intermediate 149.2 as a colorless oil; ES-MS: M+=199.2; 1HNMR(DMSO-d6) 3.65 (s, 2H), 3.50 (dd, 2H), 3.40 (dd, 2H), 3.30-3.25 (m, 1H), 3.20 (s, 3H), 2.70-2.60 (m, 2H), 2.25-2.20 (m, 2H), 1.85-1.80 (m, 2H), 1.50-1.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH3:19])=[CH:13]3)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc2cc(Oc3ccnc(Cl)n3)ccc2[nH]1
Yield: 75 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-hydroxy-2-methylindole (1 mmol) in 5 ml EtOH was added Et3N (1 mmol). The reaction mixture was refluxed for 5 h. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting oil residue was purified by column chromatography to give 5-(2-chloropyrimidin-4-yloxy)-2-methyl-1H-indole in a yield of 75%.