Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH:1](=[O:16])([O-:15])[O:2][C:3](CC)([CH2:11][CH3:12])[N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7].[OH-].[Na+:18]>O>[PH:1](=[O:15])([O-:16])[O:2][CH:3]([CH2:11][CH3:12])[N:4]([CH2:5][CH2:6][OH:7])[CH2:8][CH2:9][OH:10].[Na+:18]
Reactant: CCC(CC)(O[PH](=O)[O-])N(CCO)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(O[PH](=O)[O-])N(CCO)CCO
Temperature: 80 °C

Procedure:
This intermediate was prepared by adding 256 parts of diethyl-N,N-bis(hydroxyethyl)aminomethyl phosphonate to a 14% by weight solution of sodium hydroxide in water in a stirred reactor equipped with a distillation column and heating the mixture slowly to cause distillation of by-product ethanol to begin. The column temperature was maintained at 72°-75° C. and the reactor temperature was maintained at 80° C. until distillation stopped. The pH of the cooled product was 10.1 and the percent solids was 51.7.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:28])[CH3:27].COC1C=CC(C=O)=CC=1>CCOC(C)=O.CN(C=O)C>[Si:29]([O:1][CH2:2][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)([C:26]([CH3:28])([CH3:27])[CH3:25])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)COC1CCCCO1
Agent: COc1ccc(C=O)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
To a 5 L three neck flask fitted with a thermometer, mechanical stirrer, under argon was added 3 (108 g, 0.39 mol) and DMF (700 mL). To the light yellow solution was added imidazole (53 g, 0.78 mol) and TBDPSCl (tert-butyldiphenylchlorosilane) (150 mL, 0.58 mol). The solution turned cloudy and colorless. After stirring 18 hours the reaction was shown to be complete by TLC (EtOAc:hexanes; 3:7, anisaldehyde dip reagent). The clear yellow solution was concentrated under reduced pressure to a yellow residue (415 g). The residue was dissolved in diethyl ether (2 L) in a 4 L flask with a mechanical stirrer. To this solution was added 1.2M HCl (300 mL) to pH 3-4. The solution was stirred for 10 min. The layers were separated and the organic layer was washed with sat. NaHCO3 (300 mL) to pH 7 and brine (400 mL). The organic layer was dried over MgSO4 (60 g), filtered and concentrated under reduced pressure to 248 g of an oil. The oil was flashed chromatographed in portions over flash silica as follows. The oil (60 g) was flash chromatographed over flash silica gel (440 g) with anhydrous Na2SO4 (100 g) on top of the column packed with hexanes. Fractions of 500 mL were collected. Fractions 1-2 were eluted with hexanes, 3-10 with 4% ethyl acetate in hexanes, 11-18 with 10% ethyl acetate in hexanes. Fractions were monitored by TLC (EtOAc:hexanes; 2:8, anisaldehyde dip reagent) and HPLC. Fractions 9-18 were combined and concentrated under reduced pressure to give 37 g (18%) of product 4 as a viscous colorless oil. HPLC analysis showed a purity of 98%. The total weight of product 4 after purifications was 164 g (82%). 1H NMR (60 MHz, CDCl3) δ 7.0-7.7 (m, 10H), 3.2-5.2 (m, 9H), 1.0-2.0 (m, 24H).
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][C:17]([Cl:34])=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([OH:23])=O)[N:19]=1)=[O:13].[NH2:35][CH:36]1[C:46](=[O:47])[N:38]2[C:39]([C:43]([OH:45])=[O:44])=[CH:40][CH2:41][S:42][C@H:37]12.C[Si](C)(C)NC(=O)C.C(=O)(O)[O-].[Na+].Cl>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][C:17]([Cl:34])=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([NH:35][CH:36]2[C:46](=[O:47])[N:38]3[C:39]([C:43]([OH:45])=[O:44])=[CH:40][CH2:41][S:42][C@H:37]23)=[O:23])[N:19]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Agent: C[N+](C)=CCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(NC=O)sc1Cl
Yield: 87 %

Procedure:
Vilsmeier reagent prepared from N,N-dimethylformamide (0.46 ml) and phosphorous oxychloride (0.55 ml) was suspended in dry tetrahydrofuran (20 ml). To the suspension was added 2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (1.8 g) under ice-cooling with stirring and then the solution was stirred at the same temperature for an hour to prepare the activated acid solution. To the solution of 7-amino-3-cephem-4-carboxylic acid (1.1 g) and N-trimethylsilylacetamide (6.5 g) in methylene chloride (20 ml) was added the activated acid solution obtained above all at once at -20° C., and the solution was stirred at -20° C. to -10° C. for an hour. After water and ethyl acetate were added to the resultant solution, the mixed solution was adjusted to pH 7.3 with a saturated aqueous solution of sodium bicarbonate. Then the aqueous layer was adjusted to pH 2.0 with conc. hydrochloric acid, extracted with mixed solvent of ethyl acetate (100 ml) and tetrahydrofuran (50 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removing the solvent, diisopropyl ether was added to the residue. The insoluble residue was collected by filtration to give 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) (2.35 g), mp 145° to 149° C. (dec.).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3]1.O[C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][CH:26]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:32]([O:31][C:29]([C:28]1[CH:39]=[CH:40][C:25]([O:1][C@@H:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:3]2)=[CH:26][CH:27]=1)=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc(C(=O)OCc3ccccc3)cc2)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a solution of 2-benzyl 1-tert-butyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (565 mg) in tetrahydrofuran (10.0 mL) were added benzyl 4-hydroxybenzoate (405 mg) and 1,1′-(azodicarbonyl)dipiperidine (555 mg), and then tri-n-butyl phosphine (0.540 mL) was added thereto under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-benzyl 1-tert-butyl (2S,4S)-4-{4-[(benzyloxy)carbonyl]phenoxy}pyrrolidine-1,2-dicarboxylate (273 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[CH:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:21][N:22]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[C:11]2[N:10]=1.CO.CN(C=O)C.C[Si]([N:54]=[N+:55]=[N-:56])(C)C>[Cu]I.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]3[CH:20]=[N:56][NH:55][N:54]=3)[CH:15]=[CH:14][C:13]=2[C:12]2=[N:21][N:22]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[C:11]2[N:10]=1
Reactant: C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(-c4cn[nH]n4)ccc32)c1NC1CCN(S(C)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
239 mg of 5-(2,6-difluorophenyl)-3-([1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-ethynyl-2H-pyrazolo[4,3-c]isoquinoline, prepared in step 4 of example 7, are introduced into 4 ml of methanol and 4 ml of DMF, and 208 μL of trimethylsilyl azide and 15 mg of copper(I) iodide are added. After 2 h of heating at 100° C., 104 μl of trimethylsilyl azide and 7 mg of copper(I) iodide are added and heating at 100° C. is continued for 2 h. After cooling, the mixture is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (40-63 μm), eluting with a DCM/methanol mixture (95/05 by vol.), to give 121 mg of 5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-7-(2H-1,2,3-triazol-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-amine (yellow foam). 1H NMR: −0.04 (s, 9 H) 0.90 (m, 2 H) 1.61 (m, 2 H) 2.12 (m, 2 H) 275 (m, 2 H) 2.85 (s, 3 H) 3.57 (m, 2 H) 3.68 (m, 2 H) 4.47 (m, 1 H) 5.66 (s, 2 H) 6.49 (d, J=8.4 Hz, 1 H) 7.36 (t, J=8.0 Hz, 2 H) 7.67 (m, 1 H) 8.01 (broad s, 1 H) 8.25 (broad d, J=8.5 Hz, 1 H) 8.41 (d, J=8.5 Hz, 1 H) 8.43 (partially masked broad m, 1 H) 15.28 (broad m, 1 H).
Reaction SMILES: [C:1](=[S:3])=S.[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1)[CH3:5]>O1CCCC1>[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]=[C:1]=[S:3])[CH2:23][CH2:24]1)[CH3:5]
Reactant: CCOCCn1c(CC2CCN(CCN)CC2)nc2cccnc21
Reactant: S=C=S
Solvent: C1CCOC1
Product: CCOCCn1c(CC2CCN(CCN=C=S)CC2)nc2cccnc21
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 15 parts of carbon disulfide, 6.2 parts of N,N-methanetetraylbis[cyclohexanamine] and 90 parts of tetrahydrofuran was added dropwise a solution of 8.6 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineethanamine in tetrahydrofuran. Upon complete addition, the reaction mixture was stirred for 1 hour at room temperature. The whole was evaporated, yielding 11.2 parts (100%) of 3-(2-ethoxyethyl)-2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-3H-imidazo[4,5-b]pyridine as a residue (compound 136).
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:25]([O-])=O.[Na+]>O>[CH2:4]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]=[N:25]2)[CH2:15][CH2:16]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: c1ccc(CN2CCC(n3nnc4ccccc43)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
In this reference example, 2.0 g of 1-benzyl-4-(2-aminoanilino)-piperidine trihydrochloride obtained in the same manner as that of Reference Example 1 is dissolved in 30 ml of water and the solution is cooled to 0° C. To the cooled solution, 5 ml of a solution of 360 mg of sodium nitrite in 5 ml of water is added dropwise under the current of nitrogen gas over a period of 30 minutes. After completion of the dropwise addition, the reaction mixture is stirred at 0°-5° C. for one hour and then adjusted to pH 10.7. The reaction mixture is extracted with 30 ml of chloroform three times. The chloroform layer is washed with water and dried. The chloroform layer is concentrated to dryness under reduced pressure. The residue is subjected to silica gel chromatography [Wako Gel C-200, 150 ml, with a chloroform-methanol (10:1) as the eluent]. The eluate is concentrated to obtain 0.71 g of the desired product.
Reaction SMILES: CN(C(O[N:9]1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C1(N)C=CC=CC=1N.[CH2:42]([O:49][CH:50]1[CH2:53][CH:52]([C:54](O)=[O:55])[CH2:51]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.O>[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:54]([CH:52]1[CH2:53][CH:50]([O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:51]1)=[O:55]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)C1CC(OCc2ccccc2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)C1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
HBTU (2.06 g, 5.44 mmol) was added to a solution of diisopropyl ethylamine (1.03 mL, 5.93 mmol), o-phenylenediamine (0.54 g, 4.95 mmol), and 3-(benzyloxy)cyclobutanecarboxylic acid (1.02 g, 4.95 mmol) in DMF (20 mL) under argon atmosphere at 0° C. The mixture was stirred overnight with gradual warming to RT, then poured into water. The resulting suspension was filtered and the solid was air-dried to give N-(2-aminophenyl)-3-(benzyloxy)cyclobutanecarboxamide (1.17 g, 3.95 mmol, 80% yield) as an off-white solid.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][N:5]=1.N>CO>[N+:10]([C:9]1[C:4]([NH:1][NH2:2])=[N:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NN
Agent: N
Solvent: CO
Product: NNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Hydrazine (anhydrous, 0.75 ml, 23.9 mmol) was added to a solution of 2-chloro-3,5-dinitro-pyridine (3.42 g, 16.8 mmol) in methanol (25 mL). The resultant mixture was stirred at room temperature overnight. Solvent was evaporated, and the residue was washed with water and methanol several times to remove the impurities. A dark solid powder was obtained (3.0 g). MS (DCI/NH3) m/e: 200 (M+1). 1H NMR(DMSO-d6, 300MHz) δ: 9.25 (m, 1H), 9.06 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[CH2:24][OH:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][C@H:16]2[CH2:24][OH:25])(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: OC[C@@H]1Cc2ccccc2N1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2CO)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
4-Methoxy-2,6-dimethylbenzenesulfonic acid chloride (3.83 mmol, 1.0 eq) in DCM (5 ml) was added dropwise to a cooled (0° C.) solution of (S)-indolin-2-ylmethanol (4.60 mmol, 1.2 eq) and triethylamine (2.5 eq) in DCM (20 ml) and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with DCM and washed with water and saturated sodium chloride solution. It was dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was processed by column chromatography. Yield: 72%
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6]2)#[N:2].Cl[CH2:23][C:24]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31](C(F)(F)F)[CH:30]=2)[O:26][N:25]=1>>[C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:23][C:24]1[N:28]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=3[C:18]([F:21])([F:20])[F:19])[O:26][N:25]=1)[C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6]2)#[N:2]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: COC(=O)CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: COC(=O)CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccccc2C(F)(F)F)n1

Procedure:
Synthesized as described in Example 4 using methyl 3-[5-cyano-4-(trifluoromethyl)-1H-indol-2-yl]propanoate (Example 355A) and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.24 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.67 (m, 2H), 7.57 (d, J=8.5 Hz, 1H), 6.63 (s, 1H), 5.54 (s, 2H), 3.73 (s, 3H), 3.33 (d, J=7.7 Hz, 2H), 2.94 (d, J=7.7 Hz, 2H): MS (ES) m/z 523 (M+1).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]1[CH2:22]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>ClCCl.C(OCC)C.CCOC(C)=O>[N:36]([CH2:22][CH:10]1[CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C(CO)C1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C(CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(tert-butyldimethylsilyloxy)-3-(hydroxymethyl)piperidine-1-carboxylate from step B in dichloromethane (50 mL) was added triethylamine (6.06 g, 60 mmol) and methanesulfonyl chloride (3.43 g, 30 mmol) at 0° C. The reaction mixture was allowed to stir at room temperature for 1.5 hours. The crude mixture was diluted with diethyl ether, washed with sat. aq. sodium bicarbonate, brine, then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was dissolved in NMP (30 mL). Sodium azide (3.90 g, 60 mmol) was added in and the resulting suspension was stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc and hexanes, washed with water, brine, then dried over anhydrous sodium sulfate, filtered, concentrated to give the crude compound. MS (m/z): 271 (M-Boc+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: O=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: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-formylphenyl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, a 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the desired compound (0.1 g, 44%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH2:6])C.C[O-].[Na+].[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]#[N:20].C(O)(=O)C.Cl>CO>[NH:20]1[CH:4]=[CH:5][N:6]=[C:19]1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1
Reactant: CCOC(CN)OCC
Reactant: N#Cc1cnccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1cnc(-c2ncc[nH]2)cn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 453.1 %

Procedure:
2,2-Diethoxyethanamine (3 g, 2.25 mmol) was dissolved in dry methanol (20 mL). To this was added sodium methoxide (1.22 g, 22.5 mmol, as a 25% solution in methanol). After stirring for 25 minutes at room temperature, pyrazine-2-carbonitrile (2.37 g, 22.5 mmol) and acetic acid (1.35 g, 22.5 mmol) were added and the subsequent solution was stirred at 50° C. for 1 hour. MeOH (40 mL) and 6N HCl (12 mL) were added and the reaction was stirred at reflux overnight. The reaction mixture was cooled to room temperature and partitioned between 1:1 Et2O and water (60 mL) and the layers were separated. The aqueous layer was basified to pH 9/10 and extracted with 10% MeOH in DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated to give the desired compound (1.49 g yellow solid). 1H NMR (400 MHz, MeOH-d4) δ ppm: 7.67 (s, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.99 (d, J=2.5 Hz, 1 H), 5.72 (s, 2 H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Yield: 94.6 %

Procedure:
tert-Butyl 2-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]ethylcarbamate (40.0 g, 91.22 mmol) was dissolved in ethyl acetate (550 mL) and transferred to a Parr hydrogenation vessel charged with 5% platinum on carbon (10.68 g, 54.73 mmol, 0.03 eq). The vessel was purged with nitrogen gas and placed under hydrogen pressure (30 psi, 2.07×105 Pa) overnight. The catalyst was removed by filtration through a layer of CELITE filter aid and the filter cake was rinsed with methanol and dichloromethane. The filtrate was concentrated under reduced pressure to provide 35.25 g tert-butyl 2-[(3-amino-7-benzyloxyquinolin-4-yl)amino]ethylcarbamate.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][CH:15]=2)[CH:12]=1.[I:16]I>O.C(O)C>[I:16][C:15]1[N:14]=[CH:13][N:11]2[CH:12]=[C:7]([CH3:6])[CH:8]=[CH:9][C:10]=12
Reactant: II
Reactant: Cc1ccc2cncn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(I)ncn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
In a round-bottomed flask, sodium bicarbonate (215 mg, 2.56 mmol) was suspended in water (0.6 ml) and ethanol (1.2 ml). 6-methyl-imidazo[1,5-a]pyridine (90 mg, 0.68 mmol) was added followed by iodine (242 mg, 0.95 mmol). The dark brown suspension was stirred at room temperature overnight then quenched with 10% Na2S2O3-solution and extracted with EtOAc (2×). The organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to provide 99 mg (56%) of 1-iodo-6-methyl-imidazo[1,5-a]pyridine as a light brown solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.11 (s, 1H), 7.73 (s, 1H), 7.24 (d, J=9.4 Hz, 1H), 6.67 (d, J=9.1 Hz, 1H), 2.27 (s, 3H).