Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH3:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:21]1([CH3:29])[C:22]([CH:27]=O)=[CH:23][CH:24]=[CH:25][CH:26]=1.C([BH3-])#N.[Na+]>CC(O)=O.CO>[CH2:13]([C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:29][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[CH:3][CH:4]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)[CH3:14]
Reactant: Cc1ccccc1C=O
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-ethylpyrazole (300 mg, 1.14 mmol) and o-tolualdehyde (260 mg, 2.25 mmol) in 5% HOAc/MeOH (6 mL) at room temperature under argon, sodium cyanoborohydride (200 mg, 3.18 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then concentrated, diluted with water, extracted into ethyl acetate, washed with brine. The residue obtained on concentration was chromatographed on silica gel (eluant, gradient of 25-50% EtOAc in hexane) to provide the title compound as an oil that solidified on trituration with ether/petroleum ether (97 mg, 23%), m.p. 117-9° C. NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.5 (br, 1H); 8.1 (br, 1H); 7.4-7.2 (overlapping m, 7H), 6.7 (d,2H), 6.5 (s, 1H), 4.4 (s, 2H), 4.1 (br, 1H), 2.7 (q, 2H), 2.4 (s, 3H), 1.3 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.C1C[O:20]CC1>>[CH3:12][C:8]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2](=[O:20])[NH:3][CH:4]=[CH:5]2
Reactant: C1CCOC1
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Agent: Cl
Product: Cc1ccc2c(=O)[nH]ccc2c1[N+](=O)[O-]
Temperature: 22 °C
Yield: 87 %

Procedure:
1-chloro-6-methyl-5-nitroisoquinoline (50 g, 225 mmol) was suspended in THF (500 mL, 10 mL/g) and treated with 5 N aq HCl (500 mL, 10 mL/g). The suspension was stirred vigorously in a 2 L Morton Flask under a reflux condenser and heated with a heating mantle to reflux overnight (14 h). The resulting suspension was allowed to cool to room temperature (22° C.). The solid was removed by suction filtration and the filtrate set aside. The solid was washed with water (100 mL), Et2O (2×100 mL) and hexane (100 mL), then air-dried to afford 40 g as a light yellow powder. The reserved filtrate was concentrated in vacuo to a volume of ˜500 mL to afford a second crop of product. The second crop was washed with water (100 mL), Et2O (2×100 mL) and hexane (100 mL), then air-dried to afford 4 g as an orange powder. A total of 44 g (87% yield) of the title compound were isolated in this fashion. MS (M+H)+ 205.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]([CH3:10])[CH2:8][OH:9])=[CH:5][N:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.C(P(CCCC)CCCC)CCC.[CH3:34][O:35][C:36](=[O:49])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][C:43](O)=[CH:44][CH:45]=2)[N:40]([CH3:48])[CH:39]=1>C1(C)C=CC=CC=1>[CH3:34][O:35][C:36](=[O:49])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][C:43]([O:9][CH2:8][CH:7]([C:6]3[C:2]([CH3:1])=[N:3][N:4]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=4)[CH:5]=3)[CH3:10])=[CH:44][CH:45]=2)[N:40]([CH3:48])[CH:39]=1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(C)CO
Reactant: COC(=O)Cc1cn(C)c2cc(O)ccc12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cn(C)c2cc(OCC(C)c3cn(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12
Temperature: 0 °C
Yield: 58.6 %

Procedure:
2-[3-Methyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-propan-1-ol (150 mg, 0.5276 mmol) is dissolved into anhydrous toluene (2 mL) and cooled in an ice bath to 0° C. with stirring under nitrogen. Tributyl phosphine (200 uL, 0.7914 mmol) is added by syringe followed by 1-1′-azodicarbonyl-dipiperidine (200 mg, 0.7914 mmol). Finally, (6-Hydroxy-1-methyl-1H-indol-3-yl)-acetic acid methyl ester (145 mg, 0.6596 mmol) is then added. The reaction is allowed to stir under nitrogen at 0° C. for 1 hour, then room temperature and monitored by TLC and HPLC. Upon completion, the reaction is diluted with hexanes and allowed to stir vigorously for 10 min. The resulting white precipitate is then filtered away and the solution is concentrated under vacuum. The residue is further purified using either EtOAc/Hexanes (1:9) or Acetone/Hexanes (1:9) gradients on silica gel chromatography to yield (1-Methyl-6-{2-[3-methyl-1-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-propoxy}-1H-indol-3-yl)-acetic acid methyl ester (150 mg, 0.309 mmol) or 59%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:3].[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[N:26]=[C:25]([CH:27]4[CH2:32][CH2:31][N:30](S(CC5C=CC=CC=5)(=O)=O)[CH2:29][CH2:28]4)[NH:24][C:23]=3[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[CH:21][C:16]=2[O:15][CH2:14]1>C1COCC1.C(=O)(O)[O-].[Na+]>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:2]([N:30]1[CH2:29][CH2:28][CH:27]([C:25]2[NH:24][C:23]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[C:22]([C:20]3[CH:19]=[CH:18][C:17]4[O:13][CH2:14][O:15][C:16]=4[CH:21]=3)[N:26]=2)[CH2:32][CH2:31]1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: O=S(=O)(Cc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1Cl)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
2-Chlorobenzyl chloroformate (0.011 mL, 0.070 mmol) was added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine (0.021 g, 0.059 mmol; prepared as described in Example 11) in a mixture of THF (3 mL) and 2 M sodium bicarbonate aqueous solution (0.3 mL). The mixture was stirred at room temperature for 2 hours. Mixture was partitioned between ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated. HPLC purification eluting with acetonitrile:water gave 0.026 g (70%) of the title compound as a yellow solid. MS (ESP+) m/z 517.03 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.81 (m, 1H), 7.60 (d, 1H, J=8.2 Hz), 7.39 (m, 3H), 7.27 (m, 2H), 7.07 (dd, 1H, J=8.1, 1.8 Hz), 6.99 (d, 1H, J=1.8 Hz), 6.90 (d, 1H, J=8.1 Hz), 6.05 (s, 2H), 5.24 (s, 2H), 4.36 (m, 2H), 3.48 (m, 1H), 2.98 (m, 2H), 2.17 (m, 2H), 1.86 (m, 2H).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[NH2:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-]>CN(C)C(=O)C>[NH2:14][C:9]1[N:8]=[C:7]([NH2:15])[C:6]2[C:11](=[N:12][CH:13]=[C:4]([CH2:3][C:17]([CH2:3][C:4]3[N:5]=[C:6]4[C:11](=[N:12][CH:13]=3)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]4[NH2:15])([NH2:16])[C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[N:5]=2)[N:10]=1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: NCc1cccc2ccccc12
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CC(N)(Cc3cnc4nc(N)nc(N)c4n3)c3cccc4ccccc34)cnc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (51 mg, 0.2 mmol) in anhydrous N,N dimethylacetamide was added 1-aminomethyl-naphthalene (31.67 ul, 0.22 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 9 mg product was obtained. Yield: 15%; 1H NMR(500 MHz, DMSO-d6): δ 4.0970 (s, 4H), 4.2526 (s, 2H), 7.3530–7.3692 (dd, J1=7.25 Hz, J2=7.25 Hz, 2H), 7.439–7.5202 (m, 2H), 7.5414–7.5553 (d, J=6.94 Hz, 1H), 7.67408–7.69065 (d, J=8.285 Hz, 1H), 7.78789–7.7713 (d, J=8.285 Hz, 1H), 8.14819–8.1313 (d, J=8.44 Hz, 1H), 8.7144 (s, 2H), 8.93305 (s, 2H), 9.23424(s, 2H); ESI-MS: m/z 506 (M++1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Br)c1ccccn1
Yield: 94.4 %

Procedure:
To a solution of (2-pyridyl)acetonitrile (12.0 g, 0.10 mole) in 150 ml of carbon tetrachloride, was added 18.1 g of N-bromosuccinimide (0.10 mole) at room temperature. The mixture was refluxed for 1.5 h. The resulting precipitate was removed by filtration and the solvent was removed under reduced pressure to give the crude product, which was recrystallized from hexane to yield 18.6 g (94%) of the title compound as red crystals: mp 62-64° C.; 1H NMR (DMSO-d6) δ8.67 (d, 1H), 7.97 (t, 1H), 7.70 (d, 1H), 7.51 (td, 1H), 5.60(s,1H) ppm; IR (KBr) ν 3064, 2972, 1712, 1587, 1470, 1439, 1051, 993 cm-1 ; MS m/z 196, 198 (M+), 117 (M+ -Br); HRMS calcd for C7H5BrN2 195.9630, found 195.9645.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([N+]([O-])=O)[CH:28]=[CH:27][C:26]=4[S:34]([CH3:37])(=[O:36])=[O:35])[C:15]=3[CH3:38])=[CH:11][C:10]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.C(=N/[OH:53])/C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([OH:53])[CH:28]=[CH:27][C:26]=4[S:34]([CH3:37])(=[O:35])=[O:36])[C:15]=3[CH3:38])=[CH:11][C:10]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(-c2cc([N+](=O)[O-])ccc2S(C)(=O)=O)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: O/N=C\c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(-c2cc(O)ccc2S(C)(=O)=O)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)-5-nitrophenyl)quinolin-4-amine (3.0 mg, 4.8 μmol), (Z)-benzaldehyde oxime (1.0 μL, 9.6 μmol), 325 mesh potassium carbonate (2.7 mg, 0.019 mmol) and DMSO (9.6 μL) was heated in a microwave reactor for 45 min at 100° C. The reaction was cooled and diluted with water. The mixture was extracted with EtOAc (2×35 mL). The combined organic layers were washed with brine (1×20 mL) and dried over magnesium sulfate. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 20 min to provide 3-(4-(2,5-dimorpholinopyridin-3-ylamino)-7-fluoro-3-methylquinolin-2-yl)-4-(methylsulfonyl)phenol after extracting with satd sodium bicarbonate solution. 1H NMR (CDCl3) δ ppm 8.00 (1H, br. s.), 7.94 (1H, d, J=8.8 Hz), 7.84 (1H, d, J=7.8 Hz), 7.65 (1H, br. s.), 7.43 (1H, t, J=8.2 Hz), 6.91 (1H, d, J=8.4 Hz), 6.85 (1H, br. s.), 6.52 (1H, br. s.), 3.83-4.05 (4H, m), 3.76 (4H, t, J=4.7 Hz), 3.42 (2H, br. s.), 2.93-3.20 (9H, m), 1.99 (3H, br. s.). Mass Spectrum (ESI) m/e=594.2 (M+1).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]=[CH:7][CH:8]1[O:10][CH2:9]1.[Cl-].[NH4+]>O1CCCC1>[CH:7]([CH:8]([C:4]#[C:3][C:2]1[CH:1]=[CH:4][CH:3]=[CH:2][CH:1]=1)[CH2:9][OH:10])=[CH2:6]
Reactant: [Li]CCCC
Reactant: C=CC1CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C#Cc1ccccc1)CO
Reaction time: 0.5 h

Procedure:
40 ml of dry tetrahydrofuran and 20 ml of a 1.6 M n-butyl lithium solution were added to a nitrogen-substituted flask at −78° C., and the obtained mixture was then stirred for 30 minutes. Thereafter, 3.5 ml of a trifluoroborane tetrahydrofuran complex was slowly added dropwise to the reaction solution. The obtained solution was further stirred at −78° C. for 15 minutes, and 2.00 g of 1,3-butadiene monoepoxide was slowly added dropwise thereto. The thus obtained mixture was further stirred at −78° C. for 3 hours. Thereafter, 50 ml of a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained solution was extracted with 100 ml of ethyl acetate once and was then dried over sodium sulfate. The sodium sulfate was filtrated, and the organic layer was then concentrated. The residue was purified by flash chromatography (manufactured by Biotage AB; Isolera™), so as to obtain 1.80 g of 2-vinyl-4-phenyl-3-butyn-ol.
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](SC)=[C:14]([C:17]#[N:18])[C:15]#[N:16])=[CH:9][CH:8]=1)([O-:6])=[O:5]>CO>[NH2:16][C:15]1[NH:3][N:2]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N+:4]([O-:6])=[O:5])=[CH:8][CH:9]=2)[C:14]=1[C:17]#[N:18]
Reactant: CSC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)n[nH]c1N
Reaction time: 8 h

Procedure:
0.05 ml (1.00 mmol) of hydrazine hydrate is added dropwise to 245.3 mg (1.00 mmol) of 3-(4-nitrophenyl)-3-methylmercapto-2-cyano-acrylonitrile in 1.3 ml of methanol and the reaction mixture is then boiled for 8 hours and then concentrated by evaporation. The residue is stirred with ethyl acetate and filtered, yielding 5-amino-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile; TLC: Rf =0.14 (ethyl acetate:hexane=1:1).
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[C:18]1([C@@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: ClC(Cl)Cl
Product: C[C@@H](c1ccccc1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 74.4 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 121 mg of (S)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 2 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 240 mg of the desired product as colorless needles. Yield: 74%. m.p. 95-96° C.; [α]20D=−42.2° (C=0.386 AcOEt); MS(EI+) 323(M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 45.5 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.032 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:13]=[N:12][C:11]=1[C:22]([N:24]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:26]1)=[O:23])(OCC)=O)C.[S:50]1[CH:54]=[CH:53][N:52]=[C:51]1[CH:55]=O.[H-].[Na+]>C1COCC1.C(=O)([O-])O.[Na+]>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]1[C:10](/[CH:9]=[CH:55]/[C:51]2[S:50][CH:54]=[CH:53][N:52]=2)=[C:11]([C:22]([N:24]([CH2:46][CH:47]([CH3:48])[CH3:49])[C@H:25]2[CH2:30][C@@H:29]([C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:26]2)=[O:23])[N:12]=[N:13]1
Reactant: O=Cc1nccs1
Reactant: CCOP(=O)(Cc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1/C=C/c1nccs1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
tert-Butyl (3S,5R)-3-[({5-[(diethoxyphosphoryl)methyl]-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (470 mg) and 1,3-thiazole-2-carbaldehyde (90 mg) were dissolved in THF (4 ml), sodium hydride (50% in oil, 50 mg) was added under ice-cooling and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (327 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:8][N:7]=1)=O)C.O.[NH2:21][NH2:22]>C(O)C>[Si:13]([O:12][CH2:11][C:9]1[O:8][N:7]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[CH:10]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)on1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(=O)NN)no1
Temperature: 60 °C

Procedure:
A mixture of ethyl-5-({[tert-butyl(dimethylsilyl)]oxy}methyl)isoxazole-3-carboxylate (1.68 g, 5.9 mmol) and hydrazine hydrate (44 g, 8.8 mmol) in ethanol (30 mL) is heated to 60° C. for 4 hours. The mixture is cooled to room temperature and the solvents are removed in vacuo to yield 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)isoxazole-3-carbohydrazide as orange crystals.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[F:38][C:39]1([F:43])[CH2:42][NH:41][CH2:40]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:38][C:39]1([F:43])[CH2:42][N:41]([C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:21]=[C:20]([C:22]4[O:26][N:25]=[C:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:23]=4[C:33]([F:35])([F:34])[F:36])[O:19][N:18]=3)=[CH:15][CH:16]=2)[CH2:40]1
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCC(=O)N1CC(F)(F)C1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 13.1 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), 3,3-difluoroazetidine-HCl (6.45 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=10.6 min) to provide (R/S)-N-(3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (5 mg, 6.53 μmol, 13.12% yield): LCMS=578.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.24 (2 H, m), 7.51-7.74 (7 H, m), 5.11 (1 H, s), 4.49 (2 H, td, J=11.77, 7.04 Hz), 4.29 (2 H, t, J=12.21 Hz), 3.45-3.58 (2 H, m), 2.38-2.52 (2 H, m); HPLC peak RT=9.4 min (Method A).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[C:8]([NH:11][CH2:12][CH2:13][NH2:14])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([NH:14][CH2:13][CH2:12][NH:11][C:8](=[O:10])[CH3:9])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(=O)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCNS(=O)(=O)N(C)C
Reaction time: 0.5 h

Procedure:
A solution of 14.3 g (0.1 mole) of dimethylsulfamoyl chloride in 50 ml of methylene chloride was added dropwise to a rapidly stirred solution of 10.2 g (0.1 mole) of acetylethylene diamine and 10.1 g (0.1 mole) of triethylamine in 150 ml of methylene chloride at 25° C. After the addition was completed, the solution was stirred for 30 min and then washed in a separatory funnel with two 100 ml portions of water. The organic phase was separated, and dried over MgSO4, and then concentrated under reduced pressure to afford N-[2[(dimethylamino)sulfonylamino]ethyl]acetamide as an oil. The N-acetyl group was then removed by treatment of the oil with 100 ml of 15% HCl at 80° C. for 6 h. This solution was concentrated under reduced pressure to provide 12.6 g (73%) of product as an oil. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:26]4[CH2:25][CH2:24][C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([OH:22])[CH2:28][CH2:27]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-hydroxy4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=463.