Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[O:12]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.C([O-])(=O)C.[Na+]>C(O)C>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:14]2([O:12][C:4]3=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]3[CH2:13]2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Cn1cc([N+](=O)[O-])nc1O2
Yield: 28.7 %

Procedure:
2,4-Dinitro-1H-imidazole (1.0 g, 6.3 mmol), tert-butyl 1-oxa-6-azaspiro[2,5]octane-6-carboxylate (2.0 g, 9.5 mmol) and sodium acetate (612 mg, 7.5 mmol) in ethanol (7 ml) were stirred under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution and methylene chloride were added followed by stirring vigorously, and then the mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was crystallized from methylene chloride-diisopropyl ether to afford 1′-tert-butoxycarbonyl-2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidine] (586 mg, yield 29%) as a white powder.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([C@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[O:16][CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH2:6]2)[O:4]CC1>Cl.CC(=O)CC>[ClH:24].[O:4]=[C:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[O:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[CH2:6]1
Reactant: Clc1cccc(Cl)c1CO[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Agent: Cl
Solvent: CCC(C)=O
Product: O=C1CCN([C@H]2CCCC[C@@H]2OCc2c(Cl)cccc2Cl)C1
Yield: 72 %

Procedure:
The ketal intermediate (step vi) in a mixture of 6M HCl-butanone (1:4, v/v, 100 mL) was refluxed for 16 hours. The butanone was evaporated in vacuo and the residual aqueous layer was diluted with more water (100 mL). The acidic aqueous layer was extracted with diethyl ether (2×40 mL) and then with dichloromethane (3×40 mL). The combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to provide the crude title compound. The product was crystallized by triturating in diethyl ether and reprecipitated from a mixture of dichloromethane-diethyl ether to yield 1.8 g (72% yield) of the title compound, having the elemental analysis indicated in Table 1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@:4]([C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])([CH2:7][CH3:8])[CH2:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:39][O:40][CH:41]1[C:46](=O)[CH2:45][CH2:44][O:43][CH2:42]1.[OH-].[Na+]>ClCCl.O>[CH2:7]([C@:4]1([C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:10])[CH2:5][CH2:6][C@@H:2]([NH:1][C@@H:46]2[CH2:45][CH2:44][O:43][CH2:42][C@H:41]2[O:40][CH3:39])[CH2:3]1)[CH3:8].[C:21]([O:20][C:18]([N:14]1[CH2:13][C@@H:12]2[CH2:17][C@H:15]1[CH2:16][N:11]2[C:9]([C@@:4]1([CH2:7][CH3:8])[CH2:5][CH2:6][C@@H:2]([NH:1][C@@H:46]2[C@H:41]([O:40][CH3:39])[CH2:42][O:43][CH2:44][CH2:45]2)[CH2:3]1)=[O:10])=[O:19])([CH3:23])([CH3:22])[CH3:24]
Reactant: COC1COCCC1=O
Reactant: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)CC[C@@H](N[C@@H]2CCOC[C@H]2OC)C1
Product: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)CC[C@@H](N[C@H]2CCOC[C@H]2OC)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 0° C. solution of tert-butyl (1S,4S)-5-{[(1S,3R)-3-amino-1-ethylcyclopentyl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.58 g, 4.7 mmol) in dichloromethane (25 ml) was treated with sodium triacetoxyborohydride (2.36 g, 11.1 mmol) and 3R)-3-methoxytetrahydro-4H-pyran-4-one (0.76 g, 7.6 mmol). The reaction was stirred under nitrogen at 0° C. for 30 minutes then allowed to warm to room temperature and stirred for 15 hours. The reaction was treated with 2.5N NaOH (10 mL) and stirred for 10 minutes. The reaction was diluted with water and the layers separated. The aqueous layer was extracted twice with ethyl acetate. The dichloromethane layer was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layers were combined, washed with brine, dried over MgSO4, concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give the desired product, 1,5-anhydro-3-{[(1R,3S)-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-ethylcyclopentyl]amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol. LC/MS (M+H)=452.3124 exp, 452.3135 obs; 1H NMR (400 MHz, CDCl3) δ ppm 4.94-4.41 (2H), 4.11-4.04 (1H), 3.97-3.91 (1H), 3.53-3.18 (11H), 2.83-2.75 (1H), 2.60-2.30 (1H), 2.03-1.55 (10H), 1.48-1.37 (11H), 0.85-0.78 (3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].Cl.[OH-].[NH4+].[CH4:26]>CO.CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:17]=[C:13]([C:14]([O:16][CH3:26])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: C
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1O
Reaction time: 8 h

Procedure:
A chilled solution of 5-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]salicylic acid (148 g, 0.45 mol) in methanol is saturated with hydrogen chloride gas, warmed to and held at room temperature overnight and poured onto ice. The aqueous mixture is adjusted to about pH 7.5 with concentrated ammonium hydroxide solution and extracted with methylene chloride. The combined organic extracts are washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, treated with 10 g of silica gel, filtered and concentrated in vacuo to obtain a dark gum. The gum is dissolved in a methanol-water solution, treated with charcoal, filtered and crystallized to give the title product as an offwhite solid (102.3 g 66.2% mp 62°-64° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[C:28]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:15][N:14]=2)=[CH:4][C:3]=1[CH:30]=C.[O:32]=[O+][O-].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:29]=[C:28]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[C:17]([C:18]([F:21])([F:19])[F:20])=[C:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:15][N:14]=2)=[CH:4][C:3]=1[CH:30]=[O:32]
Reactant: O=[O+][O-]
Reactant: C=Cc1cc2c(cc1C)-c1noc(-c3noc(-c4ccccc4)c3C(F)(F)F)c1CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(cc1C=O)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 64E, 0.058 g, 0.137 mmol) in dichloromethane (10 mL) at −78° C. was passed ozone from an ozone generator until the solution turned a deep blue. The reaction mixture then was purged with oxygen until the blue color disappeared, then with nitrogen for five minutes. The reaction mixture was allowed to warm to room temperature and triethylamine (0.019 mL, 0.137 mmol) was added. The reaction mixture was stirred at room temperature for fifteen minutes and then concentrated under vacuum to give 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde as a tan solid (0.043, 0.101 mmol, 74%). The product had an HPLC ret. time=3.43 min (condition B). LC/MS M+1=425.10.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])([O-:3])=[O:2].C(N(CC)CC)C.[C:22](Cl)([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:23]>O1CCCC1>[C:7]([N:6]([C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:23])[C:5]1[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)Nc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C(C)(C)C

Procedure:
To a stirred solution of 2-nitro-N-tert-butylaniline (37 g) and triethylamine (35 ml) in tetrahydrofuran (400 ml) was added dropwise a solution of ethoxalyl chloride (25 ml) in tetrahydrofuran (50 ml). The mixture was then brought to reflux temperature for 8 h. The solvent was removed by evaporation, and the residue was partitioned between ether (300 ml) and water (500 ml). The organic phase was washed twice with water, dried over Na2SO4 and evaporated. This left the title compound as light yellow crystals, m.p. 73°-74° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[C:17]([Mg]Br)([CH3:19])=[CH2:18]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:6]=[CH:7][CH:8]=[C:9]3[CH:18]=[C:17]([CH3:19])[NH:1][C:4]=23)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1-c1ccc(F)cc1
Reactant: C=C(C)[Mg]Br
Product: Cc1cc2ccnc(-c3ccc(F)cc3)c2[nH]1
Yield: 37 %

Procedure:
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-(4-fluorophenyl)pyridine prepared in Preparation 13 and isopropenyl magnesium bromide, the titled compound was obtained as a white solid. (Yield: 37%)
Reaction SMILES: Cl(O)(=O)(=O)=O.CO[CH:8]=[C:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1.Cl.[O:18]([NH2:20])[CH3:19]>C(Cl)(Cl)Cl.O.CO>[CH3:19][O:18][N:20]=[CH:8][CH:9]1[CH:14]2[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]2)[CH2:10]1
Reactant: COC=C1CN2CCC1CC2
Reactant: CON
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CON=CC1CN2CCC1CC2

Procedure:
11 cm3 of a 70% aqueous solution of perchloric acid is added at ambient temperature to 4.6 g of 3-methoxy methylidene quinuclidine (Heterocycles 244, 4-971 (1986)) in solution in 46 cm3 of chloroform. After one hour of contact, 2.5 g of methoxylamine hydrochloride in 10 cm3 of water and 10 cm3 of methanol is added and the reaction medium is maintained in this way for one night, and is then concentrated, alkalized with 2N sodium hydroxide, extracted with ethyl acetate; the solvents are evaporated, and the residue is taken up in ethyl ether and filtered. The filtrate is distilled at 150° C. under 0.08 mbar and 3.2 g of expected product is obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:10].I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:10]
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23.0 mL of 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 mg, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65 g, 90.9%) as a yellow oil: EI-HRMS m/e calcd for C16H21Cl2O2 (M+) 280.1230, found 280.1227.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[N+](=[CH2:19])=[N-]>CO>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:19])=[O:15])=[CH:3]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CCCCCCC1=CC(O)CC1=O
Solvent: CO
Product: COC(=O)CCCCCCC1=CC(O)CC1=O

Procedure:
To 1.0 part of 3(RS)-hydroxy-5-oxocyclopent-1-eneheptanoic acid dissolved in methanol is added dropwise a 5% ethereal diazomethane solution until a slight excess of diazomethane is present. That excess is detected when the solution exhibits a persistent yellow color. The solution then is evaporated to dryness under a nitrogen atmosphere to yield methyl 3(RS)-hydroxy-5-oxocyclopent-1-eneheptanoate.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[I:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>>[I:31][C:32]1[CH:38]=[CH:37][C:35]([N:36]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:33]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: O=C1N(c2ccc(I)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2

Procedure:
White solid. MS (ESI): 571.0 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-iodo-aniline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][CH2:20][NH:21][C:22]2[C:31]3[C:26](=[N:27][CH:28]=[CH:29][N:30]=3)[N:25]=[CH:24][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=1.[CH:32]1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:62]([O-:65])([O-])=[O:63].[K+].[K+]>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:25]1[C:26]2[C:31](=[N:30][CH:29]=[CH:28][N:27]=2)[C:22]([NH:21][CH2:20][CH2:19][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)=[C:2]([CH:3]=2)[C:62]([O:65][CH3:32])=[O:63])=[N:23][CH:24]=1
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: FC(F)(F)c1ccnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2Br)c1
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 110 °C
Yield: 23.4 %

Procedure:
To a solution of {2-[3-bromo-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-pteridin-4-yl-amine (243 mg, 0.5 mmol), in methanol in a 45 mL Parr bomb was added Pd(OAc)2 (5.6 mg, 0.25 mmol), DPPB (21 mg, 0.5 mmol), and K2CO3 (138 mg, 1 mmol). The reactor was sealed and charged with 300 psi of CO. The reaction was heated to 110° C. for 15 h, cooled to ambient temperature, filtered through Celite, and concentrated in vacuo. The residue was dissolved in CH2Cl2, washed with H2O, brine, dried over Na2SO4, suction filtered and concentrated in vacuo. The residue was slurried in Et2O and pentane. The solvent was decanted to leave 5-[2-(pteridin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-benzoic acid, methyl ester (55 mg; 23% yield) as a light yellow solid: mp 171-172° C.; 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J=2.0 Hz, 1H), 8.84 (s, 1H), 8.64 (d, J=1.9 Hz, 1H), 8.23 (d, J=5.0 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.52 (dd, J=8.2, 2.2 Hz, 1H), 7.26-7.12 (m, 4H), 4.02 (dd, J=13.7, 6.9 Hz, 2H), 3.67 (s, 3H), 3.13 (t, J=7.3 Hz, 2H); ESIMS m/z 471.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:19](=[O:22])[CH2:20]Br)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:13]1([CH2:12][CH2:11][N:10]2[CH2:9][CH2:8][NH:7][CH2:20][C:19]2=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCN(CCc1ccccc1)C(=O)CBr
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNCCN1CCc1ccccc1
Reaction time: 1 h
Yield: 256.4 %

Procedure:
To a solution of 2-[(bromoacetyl)(2-phenylethyl)amino]ethyl carbamic acid tert-butyl ester (0.81 g, 2.1 mmol) in CH2Cl2 (25 mL) was added trifluoroacetic acid (2.5 mL) and the mixture stirred for 1 h. The solvent was removed in vacuo and the residue azeotroped with toluene (10 mL) and CH2Cl2 (2×10 mL). The crude amine (1.1 g) was isolated as its trifluoroacetate salt, as a pale yellow oil and used crude in the subsequent reaction.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(N(CC)CC)C>[CH3:2][C:3]1[C:4]([C:19]([F:20])([F:22])[F:21])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methyl-1-(4-piperidinyl)-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D60) (2.2 mmol), was dissolved in 1,2-dichloroethane (50 ml) and triethylamine (7 ml), tetrahydro-4H-pyran-4-one (7 eq., 15.4 mmol, 1.4 ml), sodium triacetoxyborohydride (7 eq., ˜3.2 g) were added in that order at room temperature and the mixture was stirred at room temperature for 2 hours. Reaction mixture was quenched with 10 ml of NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product. The crude obtained was dissolved again in 1,2-dichloroethane (50 ml) and triethylamine (7 ml), tetrahydro-4H-pyran-4-one (7 eq., 15.4 mmol, 1.4 ml), sodium triacetoxyborohydride (7 eq., ˜3.2 g) were added at room temperature and the mixture was stirred at room temperature for three hours. Reaction mixture was quenched with 10 ml of NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to afford 6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one, 240 mg, 30%, M++H=384, which was subsequently converted into the hydrochloride salt using HCl solution (1M in diethyl ether, 2 eq).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[F:22][C:23]1[CH:47]=[CH:46][C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]3[N:35]=[C:36]([CH2:38][O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:37]=[C:31]3[CH2:30]2)=[O:28])=[CH:25][CH:24]=1>CC#N>[F:21][C:37]1[C:36]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:35][N:32]2[CH2:33][CH2:34][N:29]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:47][CH:46]=3)=[O:28])[CH2:30][C:31]=12
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(F)c2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 21.3 %

Procedure:
N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (56 mg, 0.16 mmol) was added to a solution of 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (50 mg, 0.14 mmol) in CH3CN (2 mL). The mixture was stirred at 80° C. for 16 hours. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% MeOH to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% MeOH) to yield (3-fluoro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone (11 mg, 20% yield). C20H17F2N3O2. 1H NMR (500 MHz, CDCl3) δ ppm 4.05 (br. s., 2H), 4.20 (br. s., 2H), 4.79 (br. s., 2H), 5.05 (s, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.02 (d, J=8.1 Hz, 2H), 7.16 (t, J=8.5 Hz, 2H), 7.29 (dd, J=8.5, 7.4 Hz, 2H), 7.50 (dd, J=8.7, 5.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=3)[CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:10][CH:11]=2)[N:6]([CH3:28])[C:5]1=[O:29].Cl.C(OCC)(=O)C>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:17][CH2:16][C:15]1[CH:14]=[C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:28])[C:5](=[O:29])[N:4]([CH2:3][C:2]([CH3:1])([CH3:31])[CH3:30])[C:12]3=[CH:11][CH:10]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(CNC(=O)OC(C)(C)C)c3)nc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(CN)c3)nc21
Reaction time: 8 h

Procedure:
To a round bottom flask, tert-butyl {3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]benzyl}carbamate (14-63) (250 mg, 0.59 mmol) was dissolved in DCM (2 mL). 4M HCl in ethyl acetate (2 ml, 8 mmol) was added and allowed to stir overnight. The reaction was diluted with sodium bicarbonate, extracted with DCM (3×), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to produce 5-[3-(aminomethyl)phenyl]-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (23-1). MS (M+H)+: observed=325.2, calculated=325.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Li+].[Cl-]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:22]=[CH2:23])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2c(C(=O)OCC)sc(SC)c2C#N)cc1
Yield: 38 %

Procedure:
Combine 4-cyano-3-(4-iodo-phenyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (0.1 g, 1.0 eq) in THF (5.0 mL) and stir. Add Pd(PPh3)4 (1%), tributyl-vinyl-stannane (0.9 eq) and LiCl. Reflux the mixture overnight. Concentrate to dryness. Wash with hexane to remove excess of stannane. Add water and filter the precipitate to provide the title compound (0.04 g, Yield 38%). MS (ES+, m/e): 330 (M+1).