Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][C:2]=12.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[CH:5]=[CH:6][N:1]=[C:2]2[CH2:9][CH2:8][CH2:7][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2c1CCC2
Product: Clc1ccnc2c1CCC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
6,7-Dihydro-5H-cyclopenta[b]pyridine 1-oxide (2.5 g, 18 mmol) was mixed with phosphoryl chloride (20 mL, 200 mmol). The reaction mixture was stirred at 120° C. for 3 h. The excess POCl3 was removed under reduced pressure. The residue was diluted in 80 mL of EtOAc and neutralized with Na2CO3 solution. After filtration, the aqueous layer was extracted with EtOAc twice. The combined organic extracts were dried, filtered and concentrated under reduced pressure to give the sub-title compound (2.6 g, 93%). LCMS calc. for C8H9ClN (M+H)+: m/z=154.2. Found: 154.3.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:19]([C:21]3[C:22]([O:38][CH3:39])=[C:23]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=O)[CH:30]=4)[C:24]([CH3:28])=[C:25]([Cl:27])[CH:26]=3)[CH3:20])[N:17]=[CH:18][C:11]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:19]([C:21]3[C:22]([O:38][CH3:39])=[C:23]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]([N:2]([CH3:3])[CH3:1])=[O:37])[CH:30]=4)[C:24]([CH3:28])=[C:25]([Cl:27])[CH:26]=3)[CH3:20])[N:17]=[CH:18][C:11]=12
Reactant: CNC
Reactant: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)N(C)C)c1
Reaction time: 1 h

Procedure:
Dimethylamine (2.0 M) in THF (0.14 mL, 0.28 mmol) was added to a solution of 4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid (18.6 mg, 0.042 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature followed by the addition of triethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 hour, then quenched with water. The mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C23H25ClN7O2 (M+H)+: m/z=466.2; Found: 466.2.
Reaction SMILES: [C:1]([O:4][C@@:5]1([C:25]#[CH:26])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH2:7][CH3:8])[C@@H:20]1[C:15](=[CH:16][C:17](=O)[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2].CO.Cl.[NH2:30][OH:31].C(=O)(O)[O-].[Na+]>O>[C:1]([O:4][C@@:5]1([C:25]#[CH:26])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH2:7][CH3:8])[C@@H:20]1[C:15](=[CH:16][C:17](=[N:30][OH:31])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2]
Reactant: NO
Reactant: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=NO)CC[C@@H]4[C@H]3CC[C@@]21CC
Reaction time: 1.5 h

Procedure:
As described in Example 22, 2.4 g. of 17β-acetoxy-17α-ethynyl-18-methyl-4,15-estradien-3-one in 60 ml. of methanol and 2 ml. of water is reacted with 1.0 g. of hydroxylamine hydrochloride and 1.0 g. of sodium bicarbonate. After 1.5 hours, the reaction mixture is worked up analogously to Example 22. After the crude product has been chromatographed on silica gel with acetone-hexane, 760 mg. of 17β-acetoxy-17α-ethynyl-18-methyl-4,15-estradien-3-one oxime is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.BrC1C=C2C(=CC=1)[C:36](=[O:40])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:40][CH3:36].[N:23]1([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc(CN2CCOCC2)cc1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Product: Nc1ccc(CN2CCOCC2)cc1

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (24), 2.38 g (75.9% yield) of light brown solid is obtained from 2.0 g (7.09 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, and 1.63 g (8.5 mmol) of 4-Morpholin-4-ylmethyl-phenylamine mp 209-210° C.; MS (ESI) m/z 442.1 (M+H)+1
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:26][C:27]2[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=2[F:33])=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: Nc1cc(O)ccc1F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)n(-c2ccccc2)n1
Temperature: 50 °C
Yield: 58.9 %

Procedure:
To a stirred suspension of phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as described in example 153A) (335 mg, 1 mmol) and 3-amino-4-fluorophenol (127 mg, 1 mmol) in acetonitrile (15 mL) at rt, was added DBU (0.3 mL, 2 mmol). The mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue purified via silica gel column chromatography to afford 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (217 mg, 59%) as a solid. LC-MS (ESI) m/z 369 (M+H)+.
Reaction SMILES: Br.[OH:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.O>CS(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(O)cc1)C1CCNCC1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(O)cc1)C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 9.7 g of 4-(4-hydroxybenzoyl)piperidine hydrobromide, 6.4 g of sodium bicarbonate and 7.0 g of 3-(2-bromoethyl)indole in 90 ml of dimethylsulfoxide is stirred overnight under nitrogen at 50° C. After cooling to ambient temperature, water is added dropwise, precipitating a gummy brown solid. The supernatant solution is decanted from the solid, triturated with water, collected, and dried. Recrystallization from an ethanol-water mixture gives an off-white solid, mp 212°-214° C. (dec.) of 3-{2-[4-(4-hydroxybenzoyl)piperidyl]ethyl}indole.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:28][C:29]([OH:31])=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][C:15]1[C:16]([N+:25]([O-:27])=[O:26])=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2.[CH3:32][CH2:33]O>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][C:15]1[C:16]([N+:25]([O-:27])=[O:26])=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2
Reactant: CCO
Reactant: COc1cc(CC(=O)O)ccc1Oc1ccc2ncccc2c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(Oc2ccc3ncccc3c2[N+](=O)[O-])c(OC)c1

Procedure:
Concentrated sulfuric acid (0.32 mL, 11.3 mmol) was added to 24.2 (4 g, 11.3 mmol) in EtOH. The mixture was heated to reflux for 15 h. After cooling, EtOH was evaporated under vacuum, and the residue was treated with EtOAc (100 mL). Saturated NaHCO3 was added to neutralize the acid. The organic layer was separated, dried with MgSO4 and concentrated to give 24.3. MS ESI (pos.) m/z: 383.1 (M+H). 1H NMR (DMSO-d6) δ 8.99 (dd, 1H); 8.24 (m, 2H); 7.77 (dd, 1H); 7.29 (d, 1H); 7.21 (d, 1H); 7.18 (d, 1H); 6.96 (dd, 1H); 4.13 (q, 2H); 3.73 (s, 5H); 1.23 (t, 3H).
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([NH:19][C@H:20]([C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[CH3:45][C:46]1[C:51]([C:52]([OH:54])=[O:53])=[C:50]([NH:55][C:56](=[O:62])[C@H:57]([CH:59]([CH3:61])[CH3:60])[NH2:58])[CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O1CCCC1>[CH2:9]([O:16][C:17]([NH:19][C@H:20]([C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH:58][C@H:57]([C:56]([NH:55][C:50]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:45])[C:51]=1[C:52]([OH:54])=[O:53])=[O:62])[CH:59]([CH3:61])[CH3:60])=[O:34])=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Isobutyl chloroformate (0.17 ml) was added to a tetrahydrofuran solution (3.5 ml) containing N-benzyloxycarbonyl-L-phenylalanyl-L-proline (523 mg) and N-methylmorpholine (0.15 ml) at -15° C., and the mixture was stirred for 0.5 hour. An N,N-dimethylformamide solution (5.5 ml) containing 6-methyl-2-(L-valylamino)benzoic acid (220 mg) and N-methylmorpholine (0.12 ml) was added dropwise to the obtained reaction mixture at -15° C., and the mixture was stirred at this temperature for 0.5 hour and then at room temperature for two hours. The reaction mixture was treated by the same procedures as in item (c) of Example 1 to obtain 2-(N-benzyloxycarbonyl-L-phenylalanyl-L-prolyl-L-valyl)amino-6-methylbenzoic acid (317 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].Cl.N[CH2:11][C:12]([NH2:14])=[O:13].C([N:17](CC)CC)C.Cl>O.C(#N)C.O>[C:12]([NH:14][CH2:2][C:1]([NH:4][CH2:5][C:6]([NH2:17])=[O:8])=[O:3])(=[O:13])[CH3:11]
Reactant: CC(=O)NCC(=O)O
Reactant: CCN(CC)CC
Reactant: NCC(N)=O
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CC(=O)NCC(=O)NCC(N)=O
Temperature: 25 °C
Yield: 60.5 %

Procedure:
N-Acetylglycine (5 g, 43 mmole) and 9.5 g (86 mmole) of glycinamide hydrochloride were dissolved in a 150 mL of a mixture of water-acetonitrile (50:50), 8.65 g (86 mmole) of triethylamine (TEA) and 12.6 g (64 mmole) of 1-ethyl-3(3-dimethyl aminopropyl)carbodiimide (EDC) as a coupling reagent were added to the mixture and the mixture was refluxed for 12 hours. The mixture was left to cool at room temperature, the insoluble materials were filtered and the filtrate was evaporated to dryness in vacuum. The residue was recrystallized from a big fraction of acetonitrile to get a mixture of the product with the salt TEA:HCl, the solid crystals were dissolved in distilled water and purified from the salt by a strong cation exchange chromatography (120 plus). The water fractions were collected and the water was removed by lyophilization to get a pure product 4.5 g (26 mmole), yield of 60%.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C:5]([CH:10]=[CH2:11])([CH:8]=O)[CH2:4][CH:3]=1.[CH3:12][C:13]1[CH2:14][C:15]([CH:21]=[CH2:22])([CH:19]=O)[CH2:16][CH2:17][CH:18]=1.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>CCO.O.O>[CH3:1][C:2]1[CH2:7][CH2:6][C:5]([CH:10]=[CH2:11])([CH:8]=[N:24][OH:25])[CH2:4][CH:3]=1.[CH3:12][C:13]1[CH2:14][C:15]([CH:21]=[CH2:22])([CH:19]=[N:24][OH:25])[CH2:16][CH2:17][CH:18]=1
Reactant: NO
Reactant: C=CC1(C=O)CCC=C(C)C1
Reactant: C=CC1(C=O)CC=C(C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CC1(C=NO)CC=C(C)CC1
Product: C=CC1(C=NO)CCC=C(C)C1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of a mixture of 4-methyl-1-vinyl-cyclohex-3-enecarbaldehyde and 3-methyl-1-vinyl-cyclohex-3-ene-carbaldehyde (6:4, 1.5 g, 10 mmol), hydroxylamine hydrochloride (1.04 g, 15 mmol) and NaHCO3 (1.26 g, 15 mmol) in EtOH/Water (20 ml, 3:1) was stirred at 50° C. for 4 h. The mixture was diluted with water and extracted 3 times with MTBE. The combined org. layers were washed with water and brine, dried (MgSO4) and evaporated in vacuo. 4-Methyl-1-vinyl-cyclohex-3-enecarbaldehyde oxime and 3-methyl-1-vinyl-cyclohex-3-ene-carbaldehyde oxime was obtained after bulb-to-bulb distillation (ratio 6:4, yield 70%) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[NH:9][C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[N:9]([CH3:27])[C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCC(CC)Oc1nc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc2c1n(C)c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by methylation of 6-(1-Ethyl-propoxy)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one with lithium bis(trimethylsilyl)amide in THF, followed by quenching with methyl iodide. 1H NMR(CDCl3) d7.00(s,2H), 5.31(m,1H), 3.66(s,3H), 2.479s,3H), 2.33(s,3H), 2.06(s,6H), 1.79(m,4H), 1.01(t,6H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC(C)c2ccccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Oc1ccc(C(=O)O)cc1)c1ccccc1OCc1ccccc1
Yield: 67.7 %

Procedure:
Methyl 4-(1-(2-(benzyloxy)phenyl)ethoxy)benzoate (0.5 g, 1.4 mmol) was dissolved in THF (5 ml) and methanol (5 ml). The solution was treated with sodium hydroxide (IN, 6 ml) and the reaction heated at 60° for 3 hours. The solvent was removed at reduced pressure and the reaction mixture diluted with water and extracted with ethyl acetate. The aqueous phase was acidified (pH1) with concentrated HCl and extracted with ethyl acetate (3×). The organic phases were combined, dried (MgSO4) and evaporated to give the title compound as a white solid (0.33 g, 68%). mpt: 203-204° C.
Reaction SMILES: [F-:1].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(OCC)C>C(#N)C>[F:1][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: O=C(CBr)c1ccccc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(CF)c1ccccc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A suspension of potassium fluoride (3.091 g) and 18-crown-6-ether (0.341 g) in acetonitrile (25 mL) was stirred at 55° C. for 1 hour. α-Bromoacetophenone (5.12 g) was added to the reaction mixture, followed by stirring for 20 hours. Subsequently, diethyl ether was added to the reaction mixture, and then the insoluble matter that was formed was removed by filtration. Water was added for partitioning the filtrate. The organic layer was sequentially washed with water and saturated brine. Subsequently, the organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the residue.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[N:3]=1.[F:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(-c5ccccc5F)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Yield: 72.8 %

Procedure:
To a solution of 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (500 mg, 0.85 mmol) and 2-fluorophenylboronic acid (143.5 mg, 1.02 mmol) in p-dioxane/H2O (3:1, 15 mL) was added K2CO3 (235.5 mg, 1.71 mmol) and Pd(PPh3)4 (49 mg, 0.0427 mmol). The reaction was heated at reflux for 24 h, quenched with H2O and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 50% EtOAc in Hex) to give to 5-(3-(4-(2-fluorophenyl)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (400 mg, 72.8%). MS (ESI, pos. ion) m/z: 647.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.06-8.97 (m, 2H), 8.42-8.17 (m, 2H), 8.12-8.03 (m, 3H), 7.91 (dd, J=8, 1.6 Hz, 1H), 7.65-7.53 (m, 5H), 7.46-7.40 (m, 4H), 7.28 (m, 2H), 6.88 (d, J=8 Hz, 2H), 4.35 (d, J=8 Hz, 2H), 3.72 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([NH2:9])[CH:8]=1.C(N(CC)CC)C.C(Cl)Cl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([N:9]([S:24]([CH3:23])(=[O:26])=[O:25])[S:24]([CH3:23])(=[O:26])=[O:25])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(N(S(C)(=O)=O)S(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of 5-Methoxy-2-nitro-phenylamine (5.0 g, 0.030 mol) and Triethylamine (10.0 mL, 0.0717 mol) in Methylene chloride (100 mL, 2 mol) at 0° C. was added dropwise Methanesulfonyl chloride (5.1 mL, 0.065 mol). The mixture was stirred for 18 hours. The mixture was poured into 1N Hydrochloric Acid (200 mL). The aqueous was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The oil was purified by silica gel chromatography using 20%→100% Ethyl Acetate:Hexane solvent gradient. N-(5-Methoxy-2-nitro-phenyl)-N-(methylsulfonyl) methanesulfonamide isolated as a yellow solid (7.75 g, 80%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][C:12]#[N:13])[O:3]1.[N:14]([Sn](CCCC)(CCCC)CCCC)=[N+:15]=[N-:16]>O1CCOCC1.C(Cl)(Cl)Cl.CCCCCC>[NH:14]1[C:12]([CH2:11][CH:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2](=[O:1])[O:3]2)=[N:13][N:16]=[N:15]1
Reactant: N#CCC1OC(=O)c2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C1OC(Cc2nnn[nH]2)c2ccccc21

Procedure:
A solution of (3-oxo-1,3-dihydro-2-benzofuran-1-yl)acetonitrile (890 mg, 5.14 mmol) and azidotributyltin (1.97 ml, 7.20 mmol) in dioxane (4.0 ml) was heated at 95° C. for 17 hours. The reaction was partitioned between EtOAc and saturated NaHCO3 aqueous solution, and then washed with saturated NaHCO3 aqueous solution. The aqueous layers were combined, washed with EtOAc, then acidified with 10% HCl aqueous solution. The acidic aqueous layer was extracted with EtOAc. The combined organic layers were then washed with brine, dried with anhydrous Na2SO4, and rotary evaporated to obtain a yellow oil. The oil was dissolved in CHCl3/Hexane and allowed to crystallize, leading to 3-(1 H-tetrazol-5-ylmethyl)-2-benzofuran-1(3 H)-one as a white solid (913 mg, 82%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O([CH2:24][C:25]([F:28])([F:27])[F:26])S(C(F)(F)F)(=O)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:3]=1[CH3:9]
Reactant: Cc1nc(O)ccc1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1c(Br)ccc(=O)n1CC(F)(F)F
Temperature: 50 °C

Procedure:
To a stirred mixture of 3-bromo-6-hydroxy-2-methylpyridine (25.0 g, 133 mmol) and cesium carbonate (52.0 g, 160 mmol) in 1,4-dioxane (600 mL) was added 2,2,2-trifluoroethyl triflate (40.1 g, 173 mmol) and the resulting mixture was heated at 50° C. for 4 h and then allowed to cool to ambient temperature. The resulting mixture was filtered and the filtrate was concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 60:40, to give the title compound. MS: m/z=269.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH:16]([C:19]1[N:24]=[C:23]([CH2:25][N:26]2[C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([NH2:35])[C:29]=3[C:28]([CH3:36])=[N:27]2)[CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:29]=3[C:28]([CH3:36])=[N:27][N:26]4[CH2:25][C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:16]([CH3:17])[CH3:18])[N:24]=3)=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(N)c12
Reactant: CCOC(=O)c1cnc2cc(Cl)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
A round bottom flask containing ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate (15.22 g, 67.8 mmol) and 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine (Preparation D; 19.0 g, 67.8 mmol) in 130 mls of THF was chilled to 0° C. LiHMDS (1M in THF, 149 mls, 149 mmol) was then added by syringe over a 15 minute period. Once the addition was complete, the reaction mixture was stirred at 0° C. for 15 minutes, and then quenched with saturated ammonium chloride (250 mls). This mixture was then extracted two times with EtOAc, the extracts were dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (100% EtOAc) afforded 18.6 g (60%) of the title compound.