Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS([C:20]1[N:30]=[C:23]2[N:24]=[C:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[N:22]2[N:21]=1)(=O)=O>O1CCCC1>[CH3:29][C:25]1[CH:26]=[C:27]([CH3:28])[N:22]2[N:21]=[C:20]([O:10][CH2:9][CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11][CH2:12][OH:13])[N:30]=[C:23]2[N:24]=1
Reactant: OCCN(CCO)c1ccccc1
Reactant: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(OCCN(CCO)c3ccccc3)nc2n1
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
A mixture of N-phenyldiethanolamine (8.76 g, 48.3 mmol) and tetrahydrofuran (70 mL) was added to a 200 mL RBF under a nitrogen atmosphere with a magnetic stirring bar. Sodium hydride (60% dispersion in mineral oil) (1.93 g, 48.3 mmol) was added portion-wise (4×˜500 mg) over 10 minutes (Effervescence). The reaction was stirred for 10 minutes before 2-methanesulfonyl-5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine (9.1 g, 40.3 mmol) was added portion-wise (4×˜2.3 g) over 10 minutes (Effervescence). Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. The title compound eluted with retention time of 3.7 min. After 45 minutes the reaction was concentrated under reduced pressure then partitioned between dichloromethane (200 mL) and water (25 mL). The aqueous layer was extracted once more with dichloromethane (100 mL). The combined organic layer was washed with saturated aqueous NaCl (25 mL), dried (Na2SO4), filtered, and concentrated. The crude material was dissolved in ethyl acetate (80 mL) and extracted with 1 N HCl (80 mL) and 0.5 N HCl (10 mL). Solid NaCl was added (˜1-3 g) to the combined acidic extracts with stirring for 10 minutes. The pH was adjusted to basic with 5 N NaOH (˜23 mL) and a gummy precipitate formed. The aqueous layer was decanted into a separatory funnel, and the solid residue was rinsed with an additional 15 mL of water. The combined aqueous layers were extracted with dichloromethane (4×30 mL). The gummy precipitate was dissolved in an additional amount of dichloromethane (50 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient elution of 60-100% ethyl acetate in hexanes to afford the title compound as a white solid (8.62 g, 65% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.15 (m, 2H), 7.07 (s, 1H), 6.79 (d, 2H), 6.59 (t, 1H), 4.70 (t, 1H), 4.49 (t, 2H), 3.79 (t, 2H), 3.54 (q, 2H), 3.46 (m, 2H), 2.63 (s, 3H), 2.52 (s, 3H). EM (calc.): 327.2; MS (ESI) m/e: 328.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[N+:12]([C:15]1[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)(=O)C.CCO>[N+:12]([C:15]1[S:19][C:18]([CH:20]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=Cc1ccc([N+](=O)[O-])s1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 5-nitro-2-thiophenecarboxaldehyde (0.28 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.55 g, in 95% yield, mp: 194.5° C. 1H NMR (DMSO-d6) δ 11.99 (s, 1H), 10.18 (s, 1H), 8.63 (s, 1H), 8.11 (d, 2H), 7.78 (d, 2H), 7.53 (d, 1H), 6.86 (d, 2H). 13C NMR (DMSO-d6) δ 164.9, 162.9, 152.5, 149.0, 142.0, 132.4, 131.8, 131.1, 125.1, 117.0. Anal. Calcd for C12H9N3O4S: C, 49.48; H, 3.11; N, 14.43. Found: C, 49.55; H, 3.09; N, 14.36.
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[C:14]([CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41](=[O:43])[CH3:42])=[CH:15][C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[N:18][C:17]=2[CH:35]=1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].C(O)C>[OH:12][C:13]1[C:14]([CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41](=[O:43])[CH3:42])=[CH:15][C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[N:18][C:17]=2[CH:35]=1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1OCc1ccccc1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)N1CCCC1c1cc2c(cc1O)nc(-c1ccccn1)n2COCC[Si](C)(C)C

Procedure:
713 mg of ammonium formate and 119 mg of 20% palladium hydroxide-carbon catalyst were added to an ethanol (20 ml) solution of 1.18 g of 1-(2-(6-benzyloxy-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone, and the reaction liquid was heated under reflux for 5 hours. 157 mg of ammonium formate and 56 mg of 20% palladium hydroxide-carbon catalyst were added to the reaction liquid, and the reaction liquid was further heated under reflux for 1 hour. After cooled, the catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure. The resulting residue was diluted with 1 N hydrochloric acid, extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=100/0 to 99/1 to 98/2) to obtain the entitled compound as a brown amorphous substance.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:1]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1ccc(Cl)cc1Cl
Reaction time: 7 h
Yield: 95 %

Procedure:
Aqueous sodium hydroxide (36 ml. of 70% w/v solution) was added slowly with stirring to glacial acetic acid (39 g). The solution was then heated to reflux and a mixture of 2,4-dichlorobenzyl chloride (100 g) and tetrabutylammonium iodide (1 g) added. The mixture was heated under reflux with stirring for 7 hours. The mixture was then treated with aqueous sodium hydroxide and worked up as described in Example 1 to give 2,4-dichlorobenzyl alcohol, having a purity of 98.5% in a yield of 95.0%.
Reaction SMILES: CC(C)([O-])C.[K+].CN(C)C=O.[N+:12]([CH3:15])([O-:14])=[O:13].[Cl:16][C:17]1[CH:38]=[CH:37][C:20]2[N:21]=[C:22](NCN=O)[CH2:23][C:24](=[O:32])[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]=2[CH:18]=1>O.C(O)(=O)C>[Cl:16][C:17]1[CH:38]=[CH:37][C:20]2[NH:21][C:22](=[CH:15][N+:12]([O-:14])=[O:13])[CH2:23][C:24](=[O:32])[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]=2[CH:18]=1
Reactant: C[N+](=O)[O-]
Reactant: O=NCNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1CC(=C[N+](=O)[O-])Nc2ccc(Cl)cc2N1c1ccccc1
Reaction time: 19 h

Procedure:
Potassium t-butoxide, 10.24 g (0.092 moles) was added to a mixture of 250 ml of dimethylformamide and 50 ml of nitromethane. After stirring at room temperature for 15 min under nigrogen, 25 g (0.076 m) of 7-chloro-3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one was added and stirring was continued for an additional 19 hours. The mixture was acidified with acetic acid and diluted with water. The precipitate was filtered off, washed with water and recrystallized from methylene chloride/ethanol to give pale yellow crystals with mp 259°-261°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:34]=[CH:33][N:32](COCC[Si](C)(C)C)[N:31]=5)=[C:26]([F:43])[CH:25]=4)=[C:17]3[N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C([C@H]2COC(=O)N2C2C=CN3N=CC(C4C=CC(C5N(COCC[Si](C)(C)C)N=CN=5)=C(F)C=4)=C3N=2)C=CC=1F>>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:34]=[CH:33][NH:32][N:31]=5)=[C:26]([F:43])[CH:25]=4)=[C:17]3[N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)c(F)c5)nc34)cc2F)n1
Agent: C[Si](C)(C)CCOCn1ncnc1-c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)c(F)c4)nc23)cc1F
Product: O=C1OC[C@H](c2ccc(F)c(F)c2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Yield: 73 %

Procedure:
(S)-4-(3,4-difluorophenyl)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (30 mg, 73%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (S)-4-(3,4-difluorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one and (S)-4-(3,4-difluorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one. LCMS (APCI+) m/z 478.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH:27]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:30]2[CH2:31][CH2:32][CH2:33][CH:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: c1ccc(C2CCCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1ccc(CN2CC(CN3CCCC(c4ccccc4)CC3)C(c3ccccc3)C2)cc1
Yield: 58.7 %

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 13 mg of 4-phenyl-perhydro-azepine and 25 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 18.5 mg of the title compound. RF : 0.37 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ1.48-1.83 (m, 6H), 2.37-2.69 (m, 10H), 2.88-3.01 (m, 3H), 3.67 (ABq, J=13 Hz, 2H), 7.09-7.39 (m, 15H). Mass Spectrum (CI): 425.3 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)#[CH:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(O)C>[N:11]1([CH2:2][CH2:1][C:3]2[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: C#Cc1cccc(CO)n1
Solvent: CCO
Product: OCc1cccc(CCN2CCOCC2)n1
Yield: 22.8 %

Procedure:
(6-Ethynylpyridin-2-yl)methanol (320 mg) and morpholine (1 g) were dissolved in 3 mL of ethanol, and the solution was heated to reflux under argon atmosphere for 24 hours. After allowing the reaction to cool, the ethanol was removed under reduced pressure, and the residue was basified with aqueous sodium hydroxide, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by chromatography on silica gel (chloroform-methanol-aqueous ammonia=200:10:1) to give 122 mg of [6-(2-morpholin-4-ylethyl)pyridin-2-yl]methanol as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.Cl>C(OCC)C>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18][C:17]1[C:2]([F:1])=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[CH:16]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1F)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CC(C)C[C@H](N)COc1cc2c(cc1F)c1ccncc1c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-((9-fluoro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (25 mg, 0.056 mmol) in diethyl ether (4 mL) was added a 2M solution of hydrochloric acid in diethyl ether (42.5 μl, 0.085 mmol) at 0° C. dropwise over 10 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the crude material was taken up in water (5 mL). The aqueous layer was washed with ethyl acetate (3 mL) and treated with 10% NaHCO3 (20 mL). The resultant solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure to afford crude material which was purified via preparative TLC (40% Ethyl acetate in Hexane) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-9-fluoro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (15 mg, 0.041 mmol, 73% yield) as a white solid. LC/MS (ESI) m/e 344.2 [(M+H)+, calcd for C19H23FN3O2 344.2]; LC/MS retention time (method A): tR=1.35 min; HPLC retention time (method A): tR=8.31 min; HPLC retention time (method B): tR=8.85 min; 1H NMR (400 MHz, CD3OD) δ ppm 9.66-9.71 (m, 1H), 8.83-8.87 (m, 1H), 7.90-7.95 (m, 1H), 7.79-7.83 (m, 1H), 6.91-6.95 (m, 1H), 4.10-4.14 (m, 1H), 3.89-3.95 (m, 1H), 3.76-3.80 (m, 3H), 3.35-3.44 (m, 1H), 1.78-1.86 (m, 1H), 1.39 (t, J=7.00 Hz, 2H), 0.96-1.03 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:21]=3)[CH2:16][CH:15]2[C:38](=[O:47])[N:39]([CH2:41][CH2:42][CH2:43][CH2:44]C=C)[CH3:40])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:44][CH2:43][CH2:42][CH2:41][N:39]([CH3:40])[C:38](=[O:47])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC1C(=O)N2
Yield: 76.1 %

Procedure:
The diolefin 17d (0.95 g, 1.49 mmol) was reacted with Hoveyda Grubbs 2nd generation catalyst (135 mg) in DCE (900 ml) according to the procedure described in Example 13 step d, which gave the title compound, (0.69 g, 76%), (M+H)+609.
Reaction SMILES: [CH:1]1[C:6]([CH:7]([OH:10])[CH2:8][NH2:9])=[CH:5][CH:4]=[C:3]([OH:11])[CH:2]=1.Cl.[C:13]([NH:20][C:21](N1C=CC=N1)=[N:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN(C=O)C>[OH:10][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[CH:2][CH:1]=1)[CH2:8][NH:9][C:21]([NH:20][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCC(O)c1ccc(O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(NCC(O)c1ccc(O)cc1)NC(=O)OC(C)(C)C
Yield: 73.2 %

Procedure:
A solution of (+/−)-octopamine hydrochloride (500 mg, 2.89 mmol) and N,N′-bis(Boc)-1H-pyrazole-1-carboxamidine (1.13 g, 3.60 mmol) in DMF (10 mL) was stirred for 1 h at ambient temperatures. The reaction mixture was concentrated, and the residue was dissolved in EtOAc (60 mL). The solution was washed with 1 N KHSO4 (2×30 mL) and 5% Na2CO3 (30 mL). The organic layer was dried (Na2SO4), concentrated, and purified by flash chromatography (EtOAc/hexane 30/70→50/50) to yield the title compound as a colorless solid (836 mg, 73%). 1H NMR (CDCl3, 600 MHz): δ 11.45 (bs, 1H), 8.76 (s, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.52 (bs, 1H), 4.81-4.78 (m, 1H), 3.66-3.50 (m, 2H), 1.51 (s, 9H), 1.49 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 162.86, 157.52, 156.04, 153.19, 133.52, 127.34, 115.65, 83.83, 80.07, 73.95, 49.49, 28.41, 28.26. MS (ESI): 396.4 (M+H, 100), 340.3 (M+H−tBu, 15).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:8]=[C:9]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=3[F:34])=[CH:22][N:10]2[C:11](=[O:21])[C:12]=1[O:13][Si](C(C)(C)C)(C)C)=[O:6].Cl>CO>[Cl:33][C:29]1[C:28]([F:34])=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][C:23]1[CH:24]=[CH:25][C:9]2[N:10]([CH:22]=1)[C:11](=[O:21])[C:12]([OH:13])=[C:7]([C:5]([OH:6])=[O:4])[N:8]=2
Reactant: COC(=O)c1nc2ccc(Cc3cccc(Cl)c3F)cn2c(=O)c1O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc2ccc(Cc3cccc(Cl)c3F)cn2c(=O)c1O
Temperature: 50 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
Aqueous sodium hydroxide (0.5 M, 1.1 mL) was added to a stirred solution of the product from Example 23.2 (22 mg, 0.046 mmol) in methanol (5 mL). The mixture was stirred at 50° C. for 24 h. Then aqueous hydrochloric acid (1.0 M) was added dropwise to adjust pH to 3˜4. The methanol was evaporated under reduced pressure and the resulting solid was collected by filtration and dried in vacuo to afford the desired compound as a brown solid (13 mg, 81%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccncc1-n1nc(C(C)(C)C)cc1N
Product: Cc1ccncc1-n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 85 %

Procedure:
3-tert-Butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-amine (844 mg, 3.66 mmol) was treated with phenyl chloroformate (1.90 mL, 15.0 mmol) according to the procedure in Example 118A to afford phenyl 3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (1.09 g, 3.11 mmol, 85%). 1H NMR (300 MHz, DMSO-d6) δ 10.09 (br s, 1H), 8.53 (d, 1H), 8.43 (s, 1H), 7.44 (d, 1H), 7.39-7.34 (m, 2H), 7.22 (t, 1H), 6.98 (br s, 2H), 6.35 (s, 1H), 2.09 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH:25]([OH:28])CO)=[N:22][C:23]=4[F:24])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH:25]=[O:28])=[N:22][C:23]=4[F:24])=[C:13]([C:14]([F:16])([F:15])[F:17])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: OCC(O)c1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-{5-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]-6-fluoropyridin-2-yl}ethane-1,2-diol (32 mg, 0.081 mmol) was dissolved in acetonitrile (1 ml) and deionized water (0.5 mL), cooled to 0° C. and treated with sodium periodate (19 mg, 0.089 mmol, 1.1 equiv). The ice bath was removed and the mixture was warmed to ambient temperature and stirred for 1 hour, which was diluted with ethyl acetate (30 mL) and washed with sodium bicarbonate (2×15 mL, aqueous saturated). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.N#N.Cl[C:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]2[C:25]([CH3:28])=[N:26][O:27][C:17]=2[CH:16]([C:29]([F:32])([F:31])[F:30])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[C:25]([CH3:28])=[N:26][O:27][C:17]=3[CH:16]([C:29]([F:30])([F:32])[F:31])[N:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1ccccc1C(Cl)=NC2C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1noc2c1-c1ccccc1C(c1ccc(F)cc1)=NC2C(F)(F)F
Temperature: 100 °C
Yield: 49.4 %

Procedure:
To a resealable vial was added Pd(Ph3P)4 (20.33 mg, 0.018 mmol) and 4-fluorophenylboronic acid (49.2 mg, 0.352 mmol) before the vial was sealed and evacuated/backfilled with N2 (3×). To the vial was added 6-chloro-1-methyl-4-(trifluoromethyl)-4H-benzo[c]isoxazolo[4,5-e]azepine (52.9 mg, 0.176 mmol) dissolved in toluene (500 μL) and Na2CO3 (2M, 176 μl, 0.352 mmol). The solution was heated to 100° C. for 2 h before cooling to room temperature and diluting with water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (31.2 mg, 0.087 mmol). LC/MS m/z 361 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=7.1 Hz, 1H), 7.77 (dt, J=1.7, 7.5 Hz, 1H), 7.52-7.41 (m, 4H), 7.29-7.21 (m, 2H), 5.38 (q, J=7.6 Hz, 1H), 2.56 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(N(CC)CC)C.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC(O)C.O>[CH2:25]([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCBr
Reactant: NCC(=O)O
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNCC(=O)O
Yield: 26.3 %

Procedure:
Glycine was dissolved in a 2:1 mixture by volume of IPA and water. Triethylamine and 1-bromododecane were added to the solution successively and the mixture was kept stirring for more than 7 days. After the solvent was removed, THF was added to the remaining material. Triethylamine hydrobromide was removed by filtration and the filtrate was concentrated. N-n-dodecylglycine was obtained from the concentrated solution by separation and purification by column chromatography with the yield of 26.3%.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1([CH3:24])[CH2:10][C:9]2[C:11]([CH3:23])=[C:12]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:13]([CH3:16])=[C:14]([CH3:15])[C:8]=2[O:7]1.Br[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:5][C:6]1([CH3:24])[CH2:10][C:9]2[C:11]([CH3:23])=[C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][CH2:22]3)[C:13]([CH3:16])=[C:14]([CH3:15])[C:8]=2[O:7]1
Reactant: Brc1ncccn1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(c3ncccn3)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 120 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of DMSO (12 mL) containing 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (1.1 g, 4.00 mmol) synthesized in Reference Example 61, 2-bromopyrimidine (954 mg, 6.0 mmol) and diisopropylethylamine (2.09 mL) were added, and the mixture was stirred at 120° C. for 2 hours. The reaction solution was diluted with ethyl acetate, and washed with water and saturated saline. The organic layer was dried using magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 9:1). The obtained solid was recrystallized from ethanol-water to obtain 600 mg of the title compound (yield 42%).