Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)[N:21]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([C:22]3[N:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:31][N:30]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2]
Reactant: Nc1ccc(-c2cccnn2)cn1
Reactant: N#Cc1cc(CC(=O)O)ccc1-c1ccnc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(CC(=O)Nc2ccc(-c3cccnn3)cn2)ccc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 206-6 (38 mg, 0.15 mmol), was dissolved in DMF (2 mL), 5-(pyridazin-3-yl)pyridin-2-amine (31 mg, 0.18 mmol) and DIEA (131 uL, 0.75 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (86 mg, 0.23 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 214. MS m/z 411.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.23 (dd, 1H), 9.13 (d, 1H), 8.56 (dd, 1H), 8.42 (d, 1H), 8.30 (dd, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.86-7.78 (m, 2H), 7.74 (d, 1H), 7.63 (dt, 1H), 7.50 (s, 1H), 3.97 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]5[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=[O:32])[CH2:27][CH2:26]5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:38])[O:4][N:3]=1.Cl.[CH2:40](N(CC)CC)C.C(Cl)(=O)C>CO.O1CCOCC1>[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:23]2[N:12]3[C@@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:14][O:15][C:16]4=[C:11]3[C:10](=[CH:9][CH:8]=[C:7]4[C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:38])[N:24]=2)[CH2:26][CH2:27]1)(=[O:32])[CH3:40]
Reactant: Cc1noc(C)c1-c1ccc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(c2nc3ccc(-c4c(C)noc4C)c4c3n2[C@@H](c2ccccn2)CO4)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To the solution of tert-butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-1-carboxylate (8.8 mg, 0.017 mmol) in methanol (1 mL) was added 4.0 M hydrogen chloride in dioxane (1 ml) at room temperature. The resulting mixture was stirred at room temperature for 10 min. The solvents were then evaporated under a steam of nitrogen. Triethylamine (0.23 mL, 1.7 mmol) was added to the resulting residue, followed by acetyl chloride (0.029 mL, 0.41 mmol). The mixture was then stirred under a stream of nitrogen for 5 min at room temperature, followed by removal of solvents and residual reagents. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound (6.3 mg, 81%). LCMS for C26H28O3N5 (M+H)+: calculated m/z=458.2. found 458.2.
Reaction SMILES: C(N=C=NC1CCCCC1)C1C=CC=CC=1.[CH3:17][O:18][CH2:19][C:20]([OH:22])=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][C:33]2[C:34]([CH3:45])=[N:35][NH:36][C:37]=2[CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:31]=1)[C:27]#[N:28]>ClCCl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][C:33]2[C:34]([CH3:45])=[N:35][NH:36][C:37]=2[CH2:38][N:39]2[CH2:40][CH2:41][N:42]([C:20](=[O:22])[CH2:19][O:18][CH3:17])[CH2:43][CH2:44]2)[CH:31]=1)[C:27]#[N:28]
Reactant: COCC(=O)O
Reactant: Cc1n[nH]c(CN2CCNCC2)c1Oc1cc(Cl)cc(C#N)c1
Agent: C(=NCc1ccccc1)=NC1CCCCC1
Solvent: ClCCl
Product: COCC(=O)N1CCN(Cc2[nH]nc(C)c2Oc2cc(Cl)cc(C#N)c2)CC1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
N-Benzyl-N′-cyclohexylcarbodiimide polymer bound (624 mg of 1.3 mmol/g, 0.480 mmol) was added in one portion to a stirred solution of methoxyacetic acid (37 μL, 0.480 mmol) and the amine of Example 78 (80 mg, 0.240 mmol) in dichloromethane (5 ml) at room temperature under nitrogen. The reaction was stirred for 1 hour and the polymer bound reagent was removed by filtration. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (45 mg) as a white foam.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27](O)=[O:28])[C:24]([CH3:30])=[CH:23][CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:45]2[C:44](=[O:46])[CH2:43][C:42]([CH3:48])([CH3:47])[CH2:41][C:40]=2[O:39][C:38]2[CH2:37][C:36]([CH3:50])([CH3:49])[CH2:35][C:34](=[O:51])[C:33]1=2.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:28])[C:24]([CH3:30])=[CH:23][CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:45]2[C:44](=[O:46])[CH2:43][C:42]([CH3:47])([CH3:48])[CH2:41][C:40]=2[O:39][C:38]2[CH2:37][C:36]([CH3:50])([CH3:49])[CH2:35][C:34](=[O:51])[C:33]1=2
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(-c2ccc(C)c(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2ccc(C)c(C(=O)NS(C)(=O)=O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 0.75 h
Yield: 84.2 %

Procedure:
1,1′-Carbonyldiimidazole (99.5 mg, 0.61 mmol) was added to a solution of the 6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]-3-methylpyridine-2-carboxylic acid produced in Example 10-3 (250 mg, 0.47 mmol) in DMF (5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 1 hour and 45 minutes. Thereafter, methanesulfonamide (58.4 mg, 0.61 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 ml, 0.61 mmol) were added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 4 hours. Thereafter, an aqueous solution of citric acid (454 mg, 2.36 mmol) was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=0:1 to 1:9, v/v). The solid thus obtained was washed with diethyl ether, followed by collection by filtration and drying, to obtain the title compound (240 mg, yield: 84%).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:16][CH3:17])=[O:15].[CH:18]1([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>[OH-].[Na+].O>[CH:25]1([NH:24][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1.[CH3:17][O:16][C:14]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5 g (30 mmol) of D-phenylalanine is dissolved in 15 ml of 2M NaOH solution, cooled to 0° C. and, simultaneously, 16.5 ml of 2M NaOH solution and 2.55 ml (33 mmol) of methyl chloroformate are added. The mixture is stirred at this temperature for 30 min, then at room temperature for 2 hours. Diluted with 40 ml of water, the mixture is washed with 10 ml of diethyl ether, acidified to pH3 with 3M HCl and extracted with 4×20 ml of ethyl acetate. The pooled organic extracts are washed with water (20 ml), dried over anhydrous sodium sulphate and evaporated at a pressure of 2.0-2.5 kPa. The residue is dissolved in 60 ml of diisopropyl ether and 6 ml (30 mmol) of dicyclohexylamine is added. The separated crystals are filtered off, washed with diisopropyl ether and dried in air.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([C:22]([O:24]CC)=[O:23])=[CH:10]2)=[O:5].[OH-].[Li+]>CO.C1COCC1>[CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:11]([C:22]([OH:24])=[O:23])=[CH:10]2)=[O:5]
Reactant: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2-c1ccccc1
Temperature: 90 °C

Procedure:
119 mg (0.31 mmol) of ethyl 5-[(3,3-dimethylbutanoyl)amino]-1-phenyl-1H-indole-2-carboxylate from Example LVIII are dissolved in each case in 2 ml of methanol and THF, and 0.31 ml (0.63 mmol) of a 2 M lithium hydroxide solution is added. The mixture is heated at 90° C. for one hour. After cooling, the mixture is, for work-up, diluted and extracted with aqueous hydrochloric acid and ethyl acetate. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
To a 0° C. solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, (6.79 g, 16 mmol) in pyridine (160 mL) was added p-toluenesulfonyl chloride (3.06 g, 16 mmol). The solution was left to warm slowly to room temperature with stirring under nitrogen. After 2.5 hours, the mixture was poured into H2O with constant stirring. The resulting off-white solid was filtered, rinsed with H2O and dried to provide the desired product (yield: 6.26 g, 79%). mp 198-200° C. 1H NMR (300 MHz, DMSO d6) δ 2.35 (s, 3H), 3.28 (s, 3H), 7.20 (m, 2H), 7.52-7.64 (M, 5H), 7.70 (m, 3H), 7.89 (m, 2H), 8.32 (s, 1H). MS APCI+531 (M+H)+, 548 (M+H2O)+, APCI−493 (M+35)−. Anal. calc. for C24H19ClN2O6S2: C, 54.29; H, 3.61; N, 5.28. Found: C, 54.55; H, 3.46; N, 5.57.
Reaction SMILES: B.[C:2]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH3:16])[C:8](=O)[C:7]2=[CH:18][S:19][CH:20]=[C:6]12)(=O)[CH3:3].Cl>O1CCCC1>[CH2:2]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH3:16])[CH2:8][C:7]2=[CH:18][S:19][CH:20]=[C:6]12)[CH3:3]
Reactant: CC(=O)N1c2cscc2C(=O)N(C)c2ccccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCN1c2cscc2CN(C)c2ccccc21

Procedure:
A 150 ml. portion of 1M-borane in tetrahydrofuran is added with stirring and cooling to a solution of 5.1 g. of 4-acetyl-4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]-benzodiazepin-10-one in 200 ml. of tetrahydrofuran. The reaction mixture is heated under reflux for 20 hours, cooled in an ice bath and 52 ml. of 6N hydrochloric acid is added dropwise with stirring. The tetrahydrofuran is removed by distillation. A 40 g. portion of sodium hydroxide pellets is carefully added in the cold with stirring followed by 25 ml. of water. The mixture is extracted with three 150 ml. portions of benzene. The benzene extracts are combined, washed with water, dried over sodium sulfate, filtered and concentrated to dryness. The residue is extracted three times with boiling hexane. The combined hexane extracts are cooled and the solid is collected, washed with hexane and ether and dried. A second crop is recovered from the hexane filtrate and combined with the first crop. The solid is dissolved in 25 ml. of methylene chloride, filtered and the solvent is evaporated almost to dryness. A 50 ml. portion of hexane is added. The solid is collected, washed with hexane and dried, giving the desired product as white crystals, mp. 135°-137° C.
Reaction SMILES: BrC1C=CC(C)=CC=1F.ClC1C(N=C=S)=CC=C(Cl)N=1.O1CCCO[CH:22]1[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:34][C:35]3[C:40]([N:41]=2)=[CH:39][CH:38]=[C:37]([C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH2:43])[N:36]=3)=[C:29]([F:50])[CH:28]=1>>[F:50][C:29]1[CH:28]=[C:27]([CH3:22])[CH:32]=[CH:31][C:30]=1[C:33]1[S:34][C:35]2[C:40]([N:41]=1)=[CH:39][CH:38]=[C:37]([C:42]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[CH2:43])[N:36]=2
Reactant: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Agent: Cc1ccc(Br)c(F)c1
Agent: S=C=Nc1ccc(Cl)nc1Cl
Product: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C)cc3F)sc2n1

Procedure:
Synthesized from 1-bromo-2-fluoro-4-methylbenzene (10 g, 53 mmol) and 2,6-dichloro-3-isothiocyanatopyridine (11 g, 53 mmol) according to the procedure for the synthesis of intermediate (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)-thiazolo[5,4-b]pyridine) to give 2-(2-fluoro-4-methylphenyl)-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine as a tan solid. MS (ESI) m/z: calculated: 346.1; Observed: 347.1 (M++1).
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([NH:15][CH2:16][CH2:17][NH:18][C:19]1[C:20]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:21][CH:22]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:24]=1)=O)(C)C>ClCCl>[NH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:20]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:21][CH:22]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:24]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added ethyl 3-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate. The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided ethyl 3-[(2-aminoethyl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1 H), 7.72 (t, J=5.8 Hz, 1 H), 7.06 (dd, J=8.4, 5.4 Hz, 2 H), 6.90 (t, J=8.7 Hz, 2 H), 6.81 (s, 1 H), 6.63 (br, 2 H), 4.27 (q, J=7.1 Hz, 2 H), 3.79 (s, 2 H), 3.45 (m, 2 H), 3.08 (m, 2 H), 1.29 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:11]2[C:12]([F:23])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:25])[CH:3]=1.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:11]2[C:12]([F:23])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)([OH:10])[C:27]([F:29])([F:28])[F:26])=[C:4]([Cl:25])[CH:3]=1
Reactant: CC(C(=O)c1cc2c(cc1F)OCC(=O)N2C)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1cc2c(cc1F)OCC(=O)N2C)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 6-[2-(4-bromo-2-chloro-phenyl)-propionyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=496.0 [M−H+].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.ClCCl.C(#N)C>[N+:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH2:4][CH2:3][CH2:2][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:6](=[O:18])[CH2:7][CH2:8]2)([O-:17])=[O:16]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCCCC1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), piperidine (355 uL, 3.59 mmol), potassium iodide (596 mg, 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into an argon purged vial fitted with a magnetic stirbar. Anhydrous acetonitrile (4 mL) was added, and the yellow suspension stirred in a heating block at a temperature of 65° C. for 18 hours. As starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a separatory funnel. The organic layer was collected, and the aqueous layer extracted twice more with dichloromethane (2×10 mL). The combined organic fractions were washed with brine (15 mL) and dried over sodium sulphate. The solution was decanted and concentrated to afford a yellow oil. The product was purified using flash chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5-5:95-97.5) to afford a yellow oil. Yield: 102 mg yellow oil (89%). 1H NMR (CDCl3) δ: 8.13 (dd, J=2.7, 9 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 4.02 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H), 2.73-2.68 (m, 2H), 2.39-2.35 (m, 6H), 1.88-1.79 (m, 2H), 1.64-1.45 (m, 6H). MS (EI): 317 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=[O:11])[CH:7]=1.[F:16][C:17]([Si](C)(C)C1C=CC=CC=1)=[CH2:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[Cs+]>C1COCC1.C(OCC)(=O)C.C(O)(=O)C.O>[F:16][C:17]([CH:10]([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:14][CH3:15])([CH3:12])[CH3:13])=[CH2:18]
Reactant: C=C(F)[Si](C)(C)c1ccccc1
Reactant: COc1ccc(F)cc1C(C)(C)CC=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=C(F)C(O)CC(C)(C)c1cc(F)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a solution of 3-(5-fluoro-2-methoxyphenyl)-3-methylbutyraldehyde (1.1 g, 5.2 mmol) and the above (1-fluorovinyl)dimethylphenylsilane (2.2 g, 12.2 mmol) in 5 mL of THF was added 0.6 mL of tetrabutylammonium fluoride (1 M in THF) and the mixture was stirred at room temperature overnight. TLC showed partial conversion to product. Cesium fluoride (0.22 g) was added and the mixture was stirred at room temperature for 3 days. 2 mL of water and 2 mL of acetic acid were added and the mixture was warmed at 60° C. for 2 hours to effect desilylation of any silylated product. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and concentrated in vacuo. Fractionation of the residue over silica gel (eluent: hexanes-dichloromethane (3:1 to 1:3 gradient) gave 0.798 g (59.5% yield) of 2-fluoro-5-(5-fluoro-2-methoxyphenyl)-5-methylhex-1-en-3-ol as an oil which was used without additional purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)CCO2
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (165) (7.5 mg, 0.03 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (12 μl, 3 eq) followed by addition of DIEA (26 μl). The resulting solution was stirred at r.t. for 1 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (150 μl) at r.t. for 1 h before worked up with EA/brine. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (166) (8.3 mg, yield: 75.3%, purity>95%) as off-white solid.
Reaction SMILES: N1C=CC=C(C=O)C=1.Cl.N12CCC(CC1)C(=O)C2.[OH-].[K+].N1C=CC=C(C=C2C(=O)C3CCN2CC3)C=1.[C:37]1([CH:43]([CH:50]2[C:55](=[O:56])[CH:54]3[CH2:57][CH2:58][N:51]2[CH2:52][CH2:53]3)[C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1([Mg]Br)C=CC=CC=1.[BH4-].[Na+]>C(O)C>[C:37]1([CH:43]([CH:50]2[CH:55]([OH:56])[CH:54]3[CH2:57][CH2:58][N:51]2[CH2:52][CH2:53]3)[C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C1C2CCN(CC2)C1C(c1ccccc1)c1cccnc1
Agent: Br[Mg]c1ccccc1
Agent: Cl
Agent: O=C1C(=Cc2cccnc2)N2CCC1CC2
Solvent: CCO
Product: OC1C2CCN(CC2)C1C(c1ccccc1)c1cccnc1

Procedure:
The manner in which 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octanes, 2-(2-phenyl-1-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octanes and 2-(3-phenyl-1-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octanes of the present invention can be synthetically produced can vary. For example, pyridine-3-carboxaldehyde and quinuclidin-3-one hydrochloride (commercially available from Aldrich) are reacted together in the presence of methanolic potassium hydroxide as described in Neilsen and Houlihan, Org. React. 16: 14-38 (1968) to give the aldol condensation product, 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one as a crystalline solid. 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one can then be converted to 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane-3-one by treatment with phenylmagnesium bromide in ethanol at −10° C. The ketone is then treated with sodium borohydride to yield the alcohol, 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-ol. This intermediate is reacted with neat thionyl chloride at room temperature to give 3-chloro-2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane as a crystalline solid. Removal of the chlorine is accomplished by hydrogenation in the presence of Raney nickel as described by de Koning, Org. Prep. Proced Int. 7:31 (1975) to give the desired product, 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane. The related compounds, 2-(2-phenyl-1-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octane and 2-(3-phenyl-1-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octane can be prepared in a similar manner by replacing phenylmagnesium bromide with benzylmagnesium bromide or 2-phenethylmagnesium bromide, respectively, in the synthetic approach given above.