Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.CC(C)([O-])C.[K+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]1([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH:5]=[C:4]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(N3CCCC3)cc(Cl)n2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc(Nc2cc(N3CCCC3)cc(-c3ccccc3)n2)cc1
Yield: 55.9 %

Procedure:
To a solution of (6-chloro-4-pyrrolidin-1-yl-pyridin-2-yl)-(4-trifluoromethoxy-phenyl)-amine (120 mg, 0.336 mmol) in 1,4-dioxane (8 mL) was added potassium-tert-butoxide (75 mg, 0.670 mmol) and tetrakis(triphenylphosphine)palladium (0) (20 mg, 0.017 mmol), followed by phenyl boronic acid (102 mg, 0.836 mmol). The resulting reaction mixture was refluxed for 10 hours, after which time water was added 100 mL to the reaction mixture, and the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel (20:80 acetone:petroleum ether) to afford the desired compound (75 mg, purity 99%, yield 6%.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].C(N(C(C)C)C(C)C)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[OH:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:18](=[O:20])[CH3:19]
Reactant: Nc1cnccc1O
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cnccc1O

Procedure:
3-Amino-pyridin-4-ol (15.0, 136 mmol) was suspended in 200 ml dichloromethane and N-ethyldiisopropylamine (82 ml, 477 mmol) was added. A solution of acetylchloride (10.6 ml, 150 mmol) in 150 ml dichloromethane was added dropwise at ambient temperature. The reaction mixture was stirred at reflux for 3 hrs and evaporated to dryness. The residue was stirred in methanol and filtered. The solvent was evaporated and the desired product was obtained as a white solid (7.2 g, 35%), MS: m/e=151.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC)=O)=C(C)[NH:10][C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2]>C(O)C>[CH2:1]([O:3][C:4](=[O:5])[CH:6]=[C:11]([CH2:12][CH3:13])[NH2:10])[CH3:2]
Reactant: CCOC(=O)C1=C(CC)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)C=C(N)CC
Yield: 71 %

Procedure:
After 8 hours' boiling of a solution of 12.5 g 3'-nitrobenzylidene-acetoacetic acid methyl ester and 7.2 g β-ethyl-β-aminoacrylic acid ethyl ester in 70 ml ethanol, 2-methyl-6-ethyl-4-(3'-nitrophenyl) 1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-ethyl ester of melting point 123°C (acetic ester/petroleum) was obtained. Yield 71% of theory.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:46][CH2:47][C:48]1[S:52][C:51]([C:53](=[N:55]O)[NH2:54])=[C:50]([CH2:57][CH3:58])[CH:49]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:57]([C:50]1[CH:49]=[C:48]([CH2:47][OH:46])[S:52][C:51]=1[C:53]1[N:55]=[C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)[O:14][N:54]=1)[CH3:58]
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 4-phenoxybenzoic acid (0.12 g, 0.53 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.55 mmol), 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d), and 1.0 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (1.0 mL, 1.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent to afford the title compound (0.17 g) in a yield of 89% as a pale yellowish crystalline solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(I)cc1Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(I)cc1Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of 4-(5-iodo-2-methyl-benzyl)phenol (12.0 g) and imidazole (3.2 g) in dimethylformamide (40 mL) is added tert-butyldimethyl-chlorosilane (6.1 g). The ice-bath is removed and the solution is stirred at ambient temperature overnight. The solution is diluted with ethyl acetate and washed twice with hydrochloric acid (1 mol/L). The organic phase is dried (sodium sulphate) and concentrated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0->20:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C1COCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(F)cc(C#N)c1

Procedure:
To a solution of commercially available 3-bromo-5-fluorobenzonitrile (5 g, 25 mmol) and triethylamine (35 ml) in 35 ml of THF was bubbled nitrogen for 10 min. Then added trimethylsilylacetylene (5.0 g, 50 mmol), copper iodide (60 mg, 0.31 mmol), and PdCl2(PPh3)2 (80 mg, 0.11 mmol) and the reaction mixture was heated with a heating mantle. After an initial exotherm, the reaction was heated at reflux for 3 hrs. The reaction mixture was concentrated on a rotary evaporator and the dark residue diluted with hexane and washed with water three times. The hexane layer was filtered through Celite and the filtrate was concentrated to give a brown oil. The crude material was used without further purification. LCMS B: Ret time 3.96 min, (M+H)+=218.14. 1H NMR, 400 MHz, CDCl3: 7.57 (s, 1H), 7.43 (m, 1H), 7.35 (m, 1H), 0.26 (s, 9H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14][OH:15])=[O:6])[CH2:3][CH2:2]1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH3:30][S:27]([O:15][CH2:14][CH2:13][CH2:12][C:11]1[N:10]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:6])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (3.57 g, 10 mmol) obtained in Example 113 and mesyl chloride (1.37 g, 12 mmol, 1.2 eq.) were dissolved in dichloromethane (50 ml) and triethylamine (1.21 g, 12 mmol, 1.2 eq.) was added dropwise over 10 min while stirring at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. The reaction mixture was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (4.25 g, 97.6%).
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH:5]([CH2:21][NH:22][C@H:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:33]C)[CH:29]=2)[C@H:24]1[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])(=[O:13])=[O:12].B(Br)(Br)Br>C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[NH2:4][CH:5]([CH2:21][NH:22][C@H:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:33])[CH:29]=2)[C@H:24]1[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])(=[O:12])=[O:13]
Reactant: COc1ccc2c(c1)CC[C@H](NCC(N)CCCCNS(=O)(=O)c1ccccc1F)[C@@H]2Cc1cccnc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: NC(CCCCNS(=O)(=O)c1ccccc1F)CN[C@H]1CCc2cc(O)ccc2[C@H]1Cc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Aminotetralin sulfonamide 8 from the previous reaction (0.160 g, 0.246 mmol) was placed in a 50 mL round-bottom flask along with a stir bar. Methylene chloride (25 mL) was added and the slurry was cooled on an ice bath for several minutes. Boron tribromide in methylene chloride (1M, 1.25 mL, 1.25 mmol) was added to the reaction. The flask was flushed with argon, capped and allowed to warm up to ambient temperature and the mixture was stirred over 16 hours at which time the reaction was quenched by the addition of methanol (1 mL). The solvents were removed in vacuo and an additional aliquot of methanol was added to the resultant residue. Evaporation of the solvent from this mixture afforded crude product which was purified via reverse-phase chromatography (Bondapak C18, 3×(40×100 mm), gradient of H2O/CH3CN (+0.1% TFA)). The appropriate fractions were collected and lyophilized. The resultant material was subsequently treated with ethanolic-hydrogen chloride, followed by evaporation and drying under vacuum to give the phenolic product 9 as a white tris-hydrochloride salt (0.145 g, 0.228 mmol). NMR(d6-DMSO): δ 10.77 (br, 1H), 10.01 (br, 1H), 9.31 (br, 1H), 8.79 (d, 1H), 8.67 (m, 4H), 8.37 (d, 1H), 7.97 (m, 2H), 7.81 (dt, 1H), 7.72 (m, 1H), 7.52-7.36 (m, 2H), 6.57 (s, 1H), 6.22 (dd, 1H), 5.69 (d, 1H), 3.79 (m, 1H), 3.68-3.30 (m, 5H), 3.04 (m, 1H), 2.92-2.68 (m, 4H), 2.33-2.10 (m, 2H), 1.73-1.56 (m, 2H), 1.55-1.32 (m, 4H); MS: MH+=527 (Scheme 30).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[C:12](Br)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[C:12]([C:29]#[N:30])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)c(Br)c1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)c(C#N)c1
Temperature: 120 °C
Yield: 25 %

Procedure:
{2-[3-bromo-4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.734 mmol, 1 eq), zinc cyanide (1.734 mmol, 1 eq), bis(tri-tbutylphosphine)palladium(0) (1.561 mmol, 0.9 eq) and zinc (0.173 mmol, 0.1 eq) were dissolved in N,N-dimethylformamide (48 ml) and heated in microwave Biotage Initiator at 120° C. for 3 min. Reaction mixture was diluted with water (200 ml) and extracted with EtOAc (7×15 ml). Crude product was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of MeOH in DCM: 0-30% for 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product {2-[3-cyano-4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.442 mmol, yield=25%, purity=91%). [M+H]=408.35 H NMR (300 MHz, CDCl3) δ/ppm 1.38 (s, 9H), 2.84 (s, 2H), 3.31-3.46 (m, 2H), 4.53-4.70 (m, 1H), 7.22 (s, 2H), 7.43-7.54 (m, 2H), 7.91-8.00 (m, 1H), 8.34-8.41 (m, 1H)
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[CH:19][CH:18]=1)=[O:15].C1(O)C=CC=CC=1>ClCCl>[F:32][C:30]([F:31])([F:33])[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:14]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][NH:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:15])=[CH:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C1CC(CNCC2CC2)CCN1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(CNCC2CC2)CC1
Reaction time: 8 h

Procedure:
Cyclopropylmethyl-piperidine-4-ylmethyl-amine (0.65 mmol, 110 mg) was dissolve in dichloromethane. 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate (0.65 mmol, 0.208 g) (prepared from the corresponding phenol by conventional methods) was added at −15° C. for 15 min and stired at room temperature overnight and evaporated to dryness. The crude product was purified by preparative HPLC (Method C) (16%, colourless crystals). HPLC-MS m/z=450.1 (M+1), Rt: 2.98 min.
Reaction SMILES: [Na].[C:2]1([P:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[C:9]1([PH:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: C1COCCO1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 10 °C
Yield: 76.2 %

Procedure:
From Sodium Diphenylphosphide. To a suspension of sodium "sand" (4.6 g, 0.2 g atom) in a 100 ml of anhydrous dioxane heated at 65°-70° C. under nitrogen, a solution of diphenyl phosphorus chloride (22 g., 0.1 ml) in 50 ml of anhydrous dioxane is added during 1 hour. The solution is heated at reflux temperature (100° C) for 4 hours until all of the sodium is consumed. Then, after cooling to 10° C. 30 ml anhydrous ethanol is dropped in, followed by 25 ml of water to dissolve the sodium chloride. The organic layer is separated and the water is extracted with ether. The organic layers are dried and distilled in vacuum giving diphenylphosphine (14.14 g, 76 percent yield).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1([CH2:16][C:17]([N:19]2[CH2:23][C@H:22]([OH:24])[CH2:21][C@H:20]2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[N:11]1([CH2:16][C:17]([N:19]2[CH2:23][C:22](=[O:24])[CH2:21][C@H:20]2[C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:32][CH:33]=2)=[O:26])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](O)CN1C(=O)Cn1cncn1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
DMSO (3.78 mmol, 0.268 mL) was added drop-wise to a flask charged with oxalyl chloride (0.165 mL, 1.89 mmol) and methylene chloride (4 mL) at −78° C. The mixture was stirred for 15 minutes and then (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide (0.20 g, 0.47 mmol), prepared as in Reference 11, in methylene chloride (1 mL) was added via syringe. The reaction mixture then was stirred at 0° C. for 30 minutes and then quenched with triethylamine (2.0 mL, 15 mmol). The mixture was stirred for an additional 5 minutes and then saturated ammonium chloride (aq., 20 mL) was added. Product was purified from the organic layer by chromatography (EtOAc to EtOAc/MeOH (9:1)+1% NEt3) to give (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-oxopyrrolidine-2-carboxamide (0.11 g, 0.25 mmol, 53% yield) as an oil.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>O.Cl>[OH2:1].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 182.1 %

Procedure:
To a suspension of 25.0 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 50 mL of water, 18 mL of concentrated hydrochloric acid was added dropwise at 28 to 39° C. The reaction mixture was stirred for 3 hours and 30 minutes at 40 to 50° C., cooled to room temperature, added with 17 mL of a 20% sodium hydroxide aqueous solution and 25 mL of water and heated to 60° C. The mixture was adjusted to pH 3 with concentrated hydrochloric acid and 25 mL of water was added thereto. Insoluble matter was filtered out at 50° C. and the filter residue was washed using 25 mL of water. The filtrate and the wash liquid were combined and heated to 40° C., added with 13.5 mL of a 20% sodium hydroxide aqueous solution, 150 mL of 2-butanone and 25 mL of water, and refluxed with heating to dissolve the solid matter. The reaction mixture was cooled to 10° C. and the solid product obtained by filtration was washed with water to give 19.3 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrate as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](F)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][OH:27]>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:27][CH3:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CO
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 2,5-difluoro-4-nitrobenzoate (Apollo, 500 mg; 2.30 mmol; 1 eq.) was dissolved in MeOH (10 mL). The solution was cooled down to 0° C. Lithium bis(trimethylsilyl)amide (2.30 mL; 1 M; 2.30 mmol; 1 eq.) was added as solution in THF. After addition, the reaction mixture was stirred at RT overnight. Solvents were evaporated and the crude mixture was dissolved in EtOAc, washed with water, brine and dried over MgSO4. The resulting crude product was purified by flash chromatography (c-hex/EtOAc 90:10), affording the title product as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 7.60-7.52 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H). HPLC (Method A) Rt 3.88 min (Purity: 88.6%).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]([C:29](OCC)=[O:30])[N:19]([CH3:28])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>>[N:2]1([NH:1][C:29]([C:18]2[N:19]([CH3:28])[C:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[C:16]([C:10]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=3[Cl:8])[N:17]=2)=[O:30])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Reactant: NN1CCCCC1
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 36, Step B (Method B), but using neat 1-aminopiperidine (3 mL), ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (30 mg, 0.073 mmol) was converted to the title compound after purification by Prep TLC (40% ethyl acetate in hexanes).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.[N:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:44]3[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=3)[C:47]([OH:49])=O)=[N:41][NH:42][CH:43]=2)=[CH:35][CH:34]=1.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(Cl)Cl.CN(C=O)C.O>[CH2:53]([NH:60][C:47](=[O:49])[C:46]1[CH:50]=[CH:51][CH:52]=[C:44]([C:40]2[C:39]([C:36]3[CH:35]=[CH:34][N:33]=[CH:38][CH:37]=3)=[CH:43][NH:42][N:41]=2)[CH:45]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(O)c1cccc(-c2n[nH]cc2-c2ccncc2)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccc(-c2n[nH]cc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.029 g, 0.15 mmol, 1.5 eq) in dry DCM (1 mL) and a solution of 1-hydroxybenzotriazole (0.020 g, 0.15 mmol, 1.5 eq) and DIPEA (0.064 g, 0.50 mmol, 5 eq) in dry DMF (0.1 mL) were added to 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzoic acid hydrochloride (0.030 g, 0.10 mmol, 1 eq) in dry DMF (0.200 ml). Benzylamine (2 eq) was added to the reaction mixture, which was stirred at room temperature for 24 h. Distilled water (1.5 mL) was poured into the suspension that was stirred for 1 h at room temperature and the organic layer was separated by filtration through Alltech Separator Tube. The solvent was evaporated and reverse phase purification of the crude afforded the final product as a solid.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([OH:20])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Yield: 83.4 %

Procedure:
Using 3-(1-cyano-1-methylethyl)-N-(3-hydroxy-4-methoxyphenyl)benzamide (1.55 mg, 5.00 mmol), 1-fluoro-4-nitrobenzene (0.78 g, 5.50 mmol) and potassium carbonate (0.69 g, 5.00 mmol), and in the same manner as in Example A18(ii), the title compound (1.80 g, 83%) was obtained as a white powder.