Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:5][CH2:6][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:8](N)=[O:9])[CH3:3].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:3][CH:2]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:8](=[O:9])[N:13]2[CH:12]([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11]1)[CH3:1]
Reactant: [H][H]
Reactant: CC(C)N(CCC(Cc1ccccn1)(C(N)=O)c1ccccc1)C(C)C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)N(CCC1(c2ccccc2)CC2CCCCN2C1=O)C(C)C
Yield: 55.6 %

Procedure:
A solution of 11.0 g (31 mmol) of the title product of Example 2 was hydrogenated at room temperature in 200 ml of glacial acetic acid using hydrogen at 60 psi over 1 g of platinum oxide catalyst. After catalyst was removed by filtration, the solvent was removed in vacuo and the residue redissolved in ice/water. The aqueous solution was made basic with dilute aqueous sodium hydroxide and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel afforded 5.9 g of the title compound as an analytically pure oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.N[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: NN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.8 %

Procedure:
A mixture of 45 g of 4-chloro-1,2-dinitrobenzene, 25 g of 4-aminomorpholine and 30 g of triethylamine in 250 ml of 96° EtOH is stirred for 48 hours at RT. The precipitate formed is filtered off and washed with iso ether to give 30.2 g of the expected product. M.p.=155° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[C:29]([Si:33]([O:36][C:37]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][C:38]=1[F:44])([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.O.CC(O)=O>[Si:33]([O:36][C:37]1[C:38]([F:44])=[C:39]([B:16]([OH:21])[OH:17])[CH:40]=[CH:41][C:42]=1[CH3:43])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:35])[CH3:34]
Reactant: Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)c(F)c1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL flask vial were added a stir-bar, 2.1 mL dry THF, and 2,2,6,6-tetramethylpiperidine (0.22 mL, 1.0 mmol). The flask was cooled to −78° Celsius and then treated with n-BuLi (0.48 mL, 1.9 mmol, 2.5 M in hexanes) over 2 minutes. The resultant mixture was stirred for 5 min and then warmed to 0° Celsius. After 30 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)3 (0.26 mL, 1.1 mmol) over 4 min. After 15 min, a solution consisting of tert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane (247 mg, 1.03 mmol) in dry THF (2.1 mL) was added over the course of 6 min and stirring continued for 1 hour at −78° Celsius. The mixture was then warmed to rt, treated with HOAc (0.5 mL), and then poured into water (100 mL) and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (3×100 mL), the combined extracts dried over Na2SO4, filtered, and concentrated to dryness to give the title compound, which was used directly in the next synthetic step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH:8]=[CH2:9]>Cl.CCCCCC>[CH2:9]([O:6][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)[CH:8]=[CH2:7]
Reactant: O=CCCCO
Reactant: C=CCO
Agent: Cl
Solvent: CCCCCC
Product: C=CCOC1CCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
The procedure of Example 1 is followed with 4-hydroxybutanal (20.0 g of 11.5 wt. % solution, 26 mmol, 1.0 eq.), allyl alcohol (3.26 g, 56 mmol, 2.2 eq.), and hexanes (50 mL). Concentrated hydrochloric acid (2 drops) is used in place of the ion-exchange resin. After 3 h of stirring at room temperature, the hexane phase contains 8.8% of 2-allyloxytetrahydrofuran (3.1 g, 92.5% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].C(O)C.[Br:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][C@H:15]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][C:34]([CH2:37][NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)[C@H:16]([NH:19][C:20](=[O:24])[CH:21]([F:23])[F:22])[CH2:17][F:18])=[O:13]>O1CCCC1>[Br-:8].[F:22][CH:21]([F:23])[C:20]([NH:19][C@H:16]([CH2:17][F:18])[C@H:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][N+:2]([CH3:4])([CH3:3])[CH3:1])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][C:34]([CH2:37][NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](OC(=O)CCCBr)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reactant: CN(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: C[N+](C)(C)CCCC(=O)O[C@H](c1ccc(-c2ccc(CNS(C)(=O)=O)nc2)cc1)[C@@H](CF)NC(=O)C(F)F
Product: [Br-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a sealed tube 4.2 M trimethylamine in ethanol (1.42 mL, 5.98 mmol) is added to a stirred solution of (1R,2S)-2-[(difluoroacetyl)amino]-3-fluoro-1-[4-(6-{[(methylsulfonyl)amino]methyl}pyridin-3-yl)phenyl]propyl 4-bromobutanoate (Step 1, 570.0 mg, 0.982 mmol) in tetrahydrofuran (11.0 mL) at room temperature and the reaction mixture was heated at 50° C. overnight. After stirring overnight the reaction mixture was concentrated and the residue was taken up in water. The aqueous layer was extracted with methylene chloride (3×) to remove all the impurities. The aqueous layer was then lyophilized overnight to afford the title compound (375 mg): 1H NMR (300 MHz, DMSO-d6) δ 1.94-1.97 (m, 2H), 2.73-2.77 (t, 2H), 3.05 (s, 9H), 3.23-3.31 (m, 2H), 3.48 (s, 3H), 4.27-4.33 (m, 1.5H), 4.43-4.53 (m, 1H), 4.67-4.71 (m, 0.5H), 4.89-4.91 (m, 1H), 5.13 (s, 2H), 5.91 (d, 1H), 6.20 (t, 1H), 7.45-7.48 (m, 3H), 7.71 (d, 2H), 8.10-8.14 (dd, 1H), 8.82 (d, 1H), 8.86 (d, 1H). MS (ESI+) m/z 559.1 [M].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:1][C:2]2[C:11]3[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc2c1CC(O)CC2
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc(Br)c1)Nc1cccc2c1CC(O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.8 %

Procedure:
To a stirred solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (500 mg, 3.06 mmol) and 3-bromophenylacetic acid (725 mg, 3.37 mmol) in DMF was added triethylamine (465 mg, 4.60 mmol), l-hydroxybenzotriazole (497 mg, 3.68 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (705 mg, 3.68 mmol). The mixture was stirred for 16 hours at room temperature. To the product mixture was added water and extracted with ethylacetate. The organic layer was washed with aqueous HCl solution then aqueous NaOH solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (hexane:acetone, 2:1) to afford 2-(3-bromophenyl)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (130 mg, 12% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@H:11]([CH2:13]I)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1.[C:32](=[O:35])([O-:34])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([OH:31])(=[O:9])/[CH:12]=[CH:11]\[C:32]([OH:34])=[O:35].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@H:11]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[C:25]5[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=5[NH:23][C:22]4=[O:31])[CH2:19][CH2:20]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc([C@H]2C[C@H](CI)CO2)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)/C=C\C(=O)O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C[C@@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 5.2 g of trans-2-(4-fluorophenyl)-4-(iodomethyl)tetrahydrofuran, 4.3 g of 1-(4-piperidyl)-5-chloro-benzimidazolin-2-one and 2.3 g of potassium carbonate in 50 ml of dimethylformamide is heated with stirring at 70° C. for 24 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in a small amount of chloroform, and a solution of 0.8 g of maleic acid in ethanol is added thereto. The crystals precipitated are collected by filtration and recrystallized from methanol to give 1-[1-(trans-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]-5-chloro-benzimidazolin-2-one maleate, melting at 208.5°-209° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=O)[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[NH2:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20]>CO>[OH:21][CH:18]([CH2:19][OH:20])[CH2:17][NH:16][C:12]([C:4]1[CH:3]=[C:2]([OH:1])[CH:11]=[C:6]([C:7]([NH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[O:9])[CH:5]=1)=[O:14]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: NCC(O)CO
Solvent: CO
Product: O=C(NCC(O)CO)c1cc(O)cc(C(=O)NCC(O)CO)c1
Temperature: 25 °C

Procedure:
Dimethyl 5-hydroxyisophthalate (12.6 g, 60 mmol) was dissolved in methanol (36 mL) containing 3-amino-1,2-dihydroxypropane (16.4 g, 180 mmol). The mixture was heated to reflux temperature for 10 days, and, after cooling to room temperature, was evaporated. Acetone (100 mL) was added to the residue and the crystalline solid was collected by filtration. The product was purified by recrystallization from acetone. Yield 9.0 g (46%).
Reaction SMILES: [N:1]([C@@H:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O-:7])=[O:6])=[C:2]=[O:3].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.[C:27]1(C)C=CC=CC=1>>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1([O:26][C:2]([NH:1][C@@H:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O:7][CH3:27])=[O:6])=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCC[C@H](N=C=O)C(=O)[O-]
Reactant: Cc1ccccc1
Reactant: OC1(c2nc3ccccc3s2)CCCC1
Product: CCCC[C@H](NC(=O)OC1(c2nc3ccccc3s2)CCCC1)C(=O)OC
Temperature: 80 °C

Procedure:
1.7 g (9.9 mmol) of (2S)-2-isocyanatohexanoate and 2.0 g (9.1 mmol) of 1-(1,3-benzothiazol-2-yl)cyclopentanol were dissolved in 5 mL of dry toluene and heated at 80° C. for 4 d. After removal of solvent, purification by silica gel column chromatography eluting with hexane:ethyl acetate (2:1) gave 3.5 g of methyl(2S)-2-[({[1-(1,3-benzothiazol-2-yl)cyclopentyl]oxy}carbonyl)amino]hexanoate as a yellow liquid, quantitatively. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8 Hz, 1H), 7.86 (d, J=8 Hz, 1H), 7.47 (t, J=8 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 5.42 (d J=8 Hz, 1H), 4.30 (m, 1H), 3.76 (s, 3H), 2.50 (m, 2H), 1.67-2.08 (m, 6H), 1.30 (m, 6H), 0.92 (t, J=8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:13]=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClCCl.[OH-].[NH4+:24].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:24][C:8]1[C:7]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CC(C)(O)Cn1cnc2cnc3cc(Br)ccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1-liter round bottom flask was charged with 1-(7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (25.0 g, 78.0 mmol), dichloromethane (400 mL) and chloroform (100 mL). To this solution was slowly added in small portions 3-chloroperoxybenxzoic acid (34.0 g of 60% purity, 117 mmol, 1.5 eq). The reaction was maintained at room temperature for 2 hours and then concentrated ammonium hydroxide solution (200 mL) was added. The mixture was vigorously stirred as p-toluenesulfonyl chloride (22.4 g, 117 mmol) was slowly added in small portions. The reaction was complete within 1 hour but was left to stir at room temperature overnight. The reaction mixture was filtered to collect a pale yellow solid. The product was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-30% CMA in chloroform). The resulting pale yellow solid was slurried in cold acetonitrile, isolated by filtration, and air-dried on the vacuum filter to provide 17.2 g of 1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with chloroform (3×100 mL). The chloroform fractions were combined, washed with brine (100 mL), dried over magnesium sulfate and concentrated to dryness to provide an additional 0.8 g of 1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol, mp>250° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([O-:22])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:26]([O:32][CH2:33]I)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([O:22][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: Cc1c(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a solution of 29.4 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 0.8 ml of dry DMF was added 0.017 ml of iodomethyl pivalate under the atmosphere of argon at −30° C., and the mixture was stirred for 4 hours during which the temperature was raised up to 10° C. The reaction mixture was diluted with 10 ml of ethyl acetate, separated, and the aqueous layer was extracted twice with ethyl acetate, while the organic layer was washed with 10 ml of semi-saturated aqueous saline. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 1 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=20:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give 7.9 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[O:14][C:7]2=[C:8]([O:12][CH3:13])[N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(#N)C>[C:1]([C:4]1[O:14][C:7]2=[C:8]([O:12][CH3:13])[N:9]=[CH:10][C:11]([Br:15])=[C:6]2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1nccc2cc(C(C)=O)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ncc(Br)c2cc(C(C)=O)oc12
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A solution of 2-acetyl-7-methoxyfuro[2,3-c]pyridine (1.1 g) in acetonitrile (50 ml) was stirred at room temperature. N-Bromosuccinimide (1.0 g) was added and stirring continued overnight. The reaction was quenched by the addition of water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with water (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 33% ethyl acetate in hexane gave the title compound (1.4 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][CH:13]=[CH:12][C:11]1=[O:16].C1(CNCC2CCCCC2)CCCCC1>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.O1CCOCC1>[F:8][C:3]1[C:2]([C:13]2[CH2:14][CH2:15][N:10]([CH3:9])[C:11](=[O:16])[CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: CN1CCC=CC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1COCCO1
Product: CN1CCC(c2cccnc2F)=CC1=O
Temperature: 100 °C

Procedure:
Into a sealed tube were placed 3-bromo-2-fluoropyridine (0.10 g, 0.60 mmol), 1-methyl-5,6-dihydropyridin-2(1H)-one (0.134 g, 1.20 mmol), bis(tri-tert-butylphosphine)palladium (0) (0.046 g, 0.09 mmol), N,N-dicyclohexylmethylamine (0.13 mL, 0.66 mmol), and 1,4-dioxane (0.5 mL). After the mixture was degassed for 5 min, the reaction was heated at 100° C. for 3 h. The cooled reaction was concentrated in vacuo, and the brown residue was directly purified via flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) to give 4-(2-fluoropyridin-3-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one as a tan solid. MS (ESI, pos. ion) m/z: 207.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH2:7][C:8]([CH3:21])([CH3:20])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)([O-])=O.[H][H]>CN(C=O)C.[Ni]>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:9][C:8]([CH3:21])([CH3:20])[CH2:7][O:6][C:5]1[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: CC(C)(COc1ccccc1[N+](=O)[O-])COc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccccc1N)COc1ccccc1N

Procedure:
343 g 1,3-bis(2-nitrophenoxy)-2,2-dimethylpropane were hydrogenated at 60° C./50 bar in 1800 ml DMF in the presence of 53 g Raney nickel. After the uptake of hydrogen had stopped, the catalyst was filtered off and the solvent was removed in vacuo.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[F:22][C:23]([F:37])([F:36])[C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 25 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine, yield 25%. White crystals, m.p. 131–132° C.; HPLC-MS: m/z: 513 (M+1) at Rt=5.0 min.; IR (KBr): ν 1722 (C═O) cm−1.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21]([CH3:27])[CH:20]=3)[N:15]=2)[CH:11]=[CH:10][C:9]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].CN[CH2:37][C:38]([OH:40])=[O:39].C(Cl)Cl>CO.C(O)(=O)C>[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:26]=[CH:25][C:22]([CH2:23][N:2]([CH3:1])[CH2:37][C:38]([OH:40])=[O:39])=[C:21]([CH3:27])[CH:20]=3)[N:15]=2)[CH:11]=[CH:10][C:9]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34]
Reactant: CNCC(=O)O
Reactant: [BH3-]C#N
Reactant: COCc1cc(-c2nc(-c3ccc(C=O)c(C)c3)no2)ccc1-c1ccccc1C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)O)c(C)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium cyanoborohydride (35 mg, 0.55 mmol) was added into a solution of 4-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)-2-methylbenzaldehyde (194 mg, 0.49 mmol) and 2-(methylamino)acetic acid (86 mg, 0.97 mmol) in a mixture of methanol (3 mL), DCM (3 mL) and acetic acid (75 μl). The mixture was stirred at room temperature overnight and the solvent was then removed in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.47-8.31 (1H, m), 8.15-8.09 (1H, m), 8.06-7.99 (2H, m), 7.69 (1H, d, J=7.9 Hz), 7.33-7.20 (4H, m), 7.11 (1H, d, J=7.4 Hz), 4.33 (2H, s), 4.21 (2H, m), 3.67 (2H, s), 3.30 (3H, s), 2.78 (3H, s), 2.54 (3H, s), 2.07 (3H, s). LC/MS (Method A): 472 (M+H)+. HPLC (Method F) Rt 3.19 min (Purity: 98.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]1([S:24]([O-:27])(=[O:26])=[O:25])[C:22](=[O:23])[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:14](=[O:15])[CH2:13]1.O.O.O.[Na+]>Cl>[CH3:11][C:12]1[C:22](=[O:23])[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:14](=[O:15])[CH:13]=1.[S:24](=[O:25])([OH:27])[O-:26].[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: CC1(S(=O)(=O)[O-])CC(=O)c2ccccc2C1=O
Agent: Cl
Agent: Nc1ccc(C(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: CC1=CC(=O)c2ccccc2C1=O
Product: O=S([O-])O
Temperature: 5 °C

Procedure:
10 g of p-amino benzoic acid were dissolved in 65 g of an 8.5% aqueous solution of hydrochloric acid. To this solution, 25 g of powdery menadione sodium bisulfite was added. After this addition, the solution was cooled to 5° C.; a white precipitate was obtained, which, after filtering, washing and vacuum drying, weighed 24 g.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1ccc(C2CCNC2)nc1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4ccccn4)C3)c(F)cc2c1=O
Yield: 88 %

Procedure:
Starting from 7-chloro 1-cyclopropyl-6-fluoro-1,4 dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.33 g, 4.7 mmol) and 2-(3 pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.64 g, 88%) as an off-white solid, mp 203°-204° C.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][CH:17]=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[CH3:28].S1C2C=CC=CC=2N=N1>>[CH3:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[C:17]1[S:16][C:14]2[C:13]([N:18]=1)=[CH:12][CH:11]=[C:10]([C:7]1([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]1)[N:15]=2)[C:24]#[N:25]
Reactant: c1ccc(C2(c3ccc4ncsc4n3)CC2)cc1
Reactant: Cc1cc(C#N)ccc1Br
Agent: c1ccc2snnc2c1
Product: Cc1cc(C#N)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1

Procedure:
3-Methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile was synthesized from 5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (48.3 mg, 191 μmol) and 4-bromo-3-methylbenzonitrile (45.0 mg, 230 μmol) according to Reference T and the general procedure for azabenzothiazole 2-arylation as a light yellow solid. MS (ESI) m/z: Calculated: 367.1; Observed: 368.1 (M++1).