Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][N:6]1[S:21]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=[O:23])=[O:22])=[O:4].[C:34]([O-:37])(=[S:36])[CH3:35].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([S:36][C:34](=[O:37])[CH3:35])[CH2:7][N:6]1[S:21]([C:24]1[CH:33]=[CH:32][C:27]2[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=1)(=[O:23])=[O:22])=[O:4]
Reactant: CC([O-])=S
Reactant: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](SC(C)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 100 °C
Yield: 83.2 %

Procedure:
5.42 g (11 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-(toluene-4-sulfonyloxy)-pyrrolidine-2-carboxylic acid methyl ester were suspended in 60 ml DMF and treated with 1.89 g (16.55 mmol, 1.5 eq) potassium thioacetate. The reaction mixture was heated to 100° C. for 45 min, cooled to RT and concentrated. The residue was redissolved in CH2Cl2/sat. NaHCO3 solution. The inorganic phase was extracted with EtOAc, the organic phases were washed with brine and dried over Na2SO4. After evaporation the residue was purified by column chromatography yielding 3.6 g (83%) (2S,4S)-4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as orange oil, MS: 394 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11](Br)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)CCCC)[CH:28]=[CH2:29]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:29]([C:11]1[N:10]=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=1)[CH:28]=[CH2:27]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(Br)nc1NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: C=CCc1cc(NCc2ccccc2)c([N+](=O)[O-])c(NCc2ccccc2)n1
Temperature: 80 °C
Yield: 77.4 %

Procedure:
N*2*,N*4*-Dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamine (1 g, 2.4 mmol) was stirred in anhydrous tetrahydrofuran (20 ml) and the solution degassed with nitrogen prior to the addition of palladium acetate (109 mg, 0.48 mmol) and allyltributyltin (1.1 ml, 3.6 mmol). The reaction mixture was degassed for 10 minutes before heating the suspension at 80° C. for 16 h. The suspension was cooled to ambient temperature, concentrated in vacuo and purified directly by column chromatography on silica, eluting with pentane:EtOAc, 9:1 to afford the title compound as a yellow solid, (696 mg, 77%)
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([N:17](CC)CC)[CH3:16].C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CCO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:17][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN(CC)CC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To 5.0 g of N-Boc-4-piperidone were added 12.6 ml of titanium isopropoxide and 9.34 ml of triethylamine. This mixture was stirred for 1 hour, then 25 ml of EtOH (abs) and 1.056 g of sodium cyanoborohydride were added. The reaction was stirred for 48 hours at room temperature. EtOH and HsO were added and the reaction mixture was filtered through Celite. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane to give 3.548 g of the title compound.
Reaction SMILES: ClC1C=C2C(C(C3C=C(OC)C(OCC4N(C)C5C=CC=CC=5N=4)=CC=3F)O)=CN([Si](C(C)C)(C(C)C)C(C)C)C2=NC=1.C(OC([N:51]1[C:55]2[CH:56]=[CH:57][C:58]([Cl:60])=[CH:59][C:54]=2[N:53]=[C:52]1[CH2:61][O:62][C:63]1[CH:68]=[C:67]([F:69])[C:66]([CH:70](O)[C:71]2[C:79]3[C:74](=[N:75][CH:76]=[CH:77][CH:78]=3)[N:73]([Si](C(C)C)(C(C)C)C(C)C)[CH:72]=2)=[CH:65][C:64]=1[O:91][CH3:92])=O)(C)(C)C>>[Cl:60][C:58]1[CH:57]=[CH:56][C:55]2[N:51]=[C:52]([CH2:61][O:62][C:63]3[CH:68]=[C:67]([F:69])[C:66]([CH2:70][C:71]4[C:79]5[C:74](=[N:75][CH:76]=[CH:77][CH:78]=5)[NH:73][CH:72]=4)=[CH:65][C:64]=3[O:91][CH3:92])[NH:53][C:54]=2[CH:59]=1
Reactant: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1nc2cc(Cl)ccc2n1C(=O)OC(C)(C)C
Agent: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(Cl)cc23)c(F)cc1OCc1nc2ccccc2n1C
Product: COc1cc(Cc2c[nH]c3ncccc23)c(F)cc1OCc1nc2ccc(Cl)cc2[nH]1
Yield: 59 %

Procedure:
6-Chloro-2-[5-fluoro-2-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzimidazole (P-2112) was prepared using the same protocol as described in Scheme 47, step 4, substituting (5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-5-methoxy-4-(1-methyl-1H-benzoimidazol-2-ylmethoxy)-phenyl]-methanol 145 with (5-chloro-2-{5-fluoro-4-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-2-methoxy-phenoxymethyl}-benzoimidazole-1-carboxylic acid tert-butyl ester 153. Purification with silica gel flash chromatography eluting with a gradient of methanol (2 to 25%) in dichloromethane gave the desired compound (P-2112, 0.052 g, 59%). MS (ESI) [M+H+]+=437.1, 439.1.
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C@H:11]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][CH2:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=2)[CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]([OH:8])[CH2:10][C@H:11]1[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][C:30]1[CH:31]=[C:32]([O:38][CH3:39])[CH:33]=[C:34]([O:36][CH3:37])[CH:35]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CCOc1ccccc1CCc1cc(OC)cc(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccccc1CCc1cc(OC)cc(OC)c1
Yield: 90.7 %

Procedure:
A solution of 0.951 g of (2R,4R)-4-benzyloxy-1-ethoxycarbonyl-2-(2-{2-[2-(3,5-dimethoxyphenyl)ethyl]phenoxy}ethyl)pyrrolidine and 95 m g of 5% w/w palladium-on-carbon in 6 ml of ethanol was stirred under an atmosphere of hydrogen at 60° C. for 9 hours. At the end of this time, the mixture was cooled, and the catalyst was removed by filtration. The filtrate was then concentrated by distillation under reduced pressure. The resulting oil was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.717 g (yield 91%) of (2R,4R)-1-ethoxycarbonyl-4-hydroxy-2-(2-{2-[2-(3,5-dimethoxyphenyl)ethyl]phenoxy}ethyl)pyrrolidine as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:44]=[N+:45]=[N-:46])(C)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)([C:22]2[CH:23]=[CH:24][C:25]([C:26]3[NH:46][N:45]=[N:44][N:27]=3)=[CH:28][CH:29]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cccc(C2(c3ccc(C#N)cc3)CCN(Cc3ccccc3)CC2)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1cccc(C2(c3ccc(-c4nnn[nH]4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzonitrile (0.24 g, 0.63 mmol) in toluene (5 mL) were added dibutyltin oxide (0.025 g, 0.1 mmol) and trimethylsilyl azide (0.15 g, 1.26 mmol). The reaction mixture was heated for 60 hours. The mixture was then cooled to room temperature and concentrated under vacuum. The residue was dissolved in methanol (5 mL) and then concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (5 mL) and ethyl acetate. The aqueous layer was washed with ethyl acetate (3×10 mL). The combined extracts were dried (MgSO4) and concentrated. Purification by flash chromatography with CH2Cl2/MeOH (9:1) afforded 0.19 g (71% yield) of 1-Benzyl-4-(3-methoxy-phenyl)4-[4-(1H-tetrazol-5-yl)-phenyl]-piperidine. 1HNMR (400 MHz, CD3OD) δ 7.95 (d, 2H), 7.44-7.41 (comp, 7H), 7.23-7.18 (m, 1H), 6.90-6.77 (comp, 2H), 6.76 (d, 1H), 6.70 (d, 1H), 4.21 (s, 2H), 3.64 (s, 3H), 3.30-2.41 (comp, 8H); MS (M+1) 426.2.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[CH:10][O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:7]2[C:11]([CH:12]=[O:13])=[CH:10][O:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cocc1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cocc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-phenyl-4-furylmethanol (Compound 19, 458 mg, 2.63 mmol), powdered 4A molecular sieves (500 mg), 4-methyl-morpholine-N-oxide (462 mg, 3.95 mmol) and tetrapropylammonium perruthenate (46 mg, 0.13 mmol) in anhydrous dichloromethane (40 ml) were stirred at room temperature for 3 hours. Residue was filtered through silica and concentrated to a brown oil which was purified by flash chromatography on silica using 10% ethyl ether/hexanes to give the titled aldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:30]#[C:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
(4-Iodo-phenyl)-carbamic acid tert-butyl ester (2.0 g, 6.27 mmol) was dissolved in THF (50 mL), treated with triethylamine (4.4 mL, 31.4 mmol), phenylacetylene (1.03 mL, 9.40 mmol), cuprous iodide (0.06 g, 0.31 mmol), and Pd(Ph3)2Cl2 (0.44 g, 0.63 mmol). The reaction was stirred overnight, then filtered and concentrated. The crude material was chromatographed on silica gel eluting with 7:1 hexane/EtOAc to give 1.48 g (80%) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2>>[CH3:28][C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[CH:20][C:19]([NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=1)=[CH:27][CH:26]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1cc2cc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)ccc2[nH]1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 5-amino-2-methylindole (41 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.66 (s, 1H), 8.75-8.72 (m, 2H), 8.08 (s, 1H), 7.46-7.34 (m, 4 H), 7.10 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 6.45 (s, 1H).
Reaction SMILES: [I-].C[N+:3]([CH2:6][C:7]1[N:11]2[C:12]([C:16]([O:18]CC)=O)=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)([CH3:5])C.[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32]CN)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>>[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:5][N:3]1[C:16](=[O:18])[C:12]2[N:11]3[C:7](=[CH:8][N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cccc2ncc(C[N+](C)(C)C)n12
Reactant: CC(C)(C)OC(=O)NCCCCCN
Agent: [I-]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCN1Cc2cnc3cccc(n23)C1=O
Yield: 54.8 %

Procedure:
A solution of 7.78 g (20 mmol) of 3-[(trimethylammonio)methyl]-5-ethoxycarbonylimidazo[1,2-a]pyridine iodide, 6.07 g (30 mmol) of 5-tert-butoxycarbonylamino-1-pentylamine and 5.58 ml (40 mmol) of triethylamine was heated for 64 hours under reflux. The solvent was distilled off. To the residue was added methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 3.93 g of the desired compound (54.9%, a pale yellow solid).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2.C(=O)([O-])O.[Na+]>CO>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([NH:13][CH:2]3[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]3)=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.8 %

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (0.85 g) and 5-aminoindazole (0.60 g) were dissolved in methanol (10 ml) thereto, and a borane-pyridine complex (0.81 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (10 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel [chloroform/methanol] to give the title compound (1.37 g) as substantially 1:1 enantiomers.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)=[CH:8][C:9]=2[CH2:11][N:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([CH2:20]CC(F)(F)F)[CH2:14][C:13]2([CH3:27])[CH3:26])[NH:4][N:3]=1.C=O>>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)=[CH:8][C:9]=2[CH2:11][N:12]2[CH2:17][C:16]([CH3:18])([CH3:19])[N:15]([CH3:20])[CH2:14][C:13]2([CH3:27])[CH3:26])[NH:4][N:3]=1
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)N(CCC(F)(F)F)CC3(C)C)c12
Agent: C=O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)N(C)CC3(C)C)c12

Procedure:
The title compound was synthesized in analogy to Example 83 (4-{3-Methyl-4-[2,2,5,5-tetramethyl-4-(3,3,3-trifluoro-propyl)-piperazin-1-ylmethyl]-1H-pyrazolo[3,4-b]pyridin-6-yl}-phenol), steps (f) and (g) using aqueous formaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[NH:8][CH:9]=[CH:10][O:11][C:5]=2[CH:4]=1.[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]1[C:7](=[O:12])[C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:11][CH:10]=[CH:9]1
Reactant: COc1ccc2c(c1)OC=CNC2=O
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC=CN(CCCCCBr)C2=O
Reaction time: 0.5 h

Procedure:
350 mg of 4,5-dihydro-8-methoxy-1,4-benzoxazepin-5-one was dissolved in 5 ml of dimethylformamide, then 88 mg (1.2 equivalents) of 60% sodium hydride was added. This was agitated for 30 minutes, then 0.60 ml (2.4 equivalents) of 1,5-dibromopentane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:10][OH:11])[C:7]([OH:9])=[O:8].Br[C:13]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>O>[C:21]([O:20][C:18]([C:13]1([O:11][N:10]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]([OH:9])=[O:8])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)C1(Br)CCCC1
Reactant: O=C(O)C(=NO)c1ccco1
Solvent: O
Product: CC(C)(C)OC(=O)C1(ON=C(C(=O)O)c2ccco2)CCCC1

Procedure:
The dipotassium salt of 2-(fur-2-yl)-2-hydroxyiminoacetic acid (syn isomer) was generated under an atmosphere of dry nitrogen and alkylated with t-butyl 1-bromocyclopentanecarboxylate using the method of Preparation 2. The product was isolated by pouring into water, acidifying and extracting in the conventional manner, thereby yielding the title compound, m.p. 106.8°-107.3°; λmax (pH 6 buffer) 277.5 nm (ε 15,100); τ(d6 -DMSO) values include 8.03, 8.30 (m, cyclopentyl protons) and 8.63 (C(CH3)3).
Reaction SMILES: [C:1]1([C:7]([NH2:12])([CH2:10][CH3:11])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.C.CO[C:20]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:23]=1)=O>C1(C)C=CC=CC=1.CO.C(Cl)Cl.O>[CH2:10]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:23]=2)=[N:12]1)[CH3:11]
Reactant: COC(=O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: CCC(N)(CN)c1ccccc1
Agent: C
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCC1(c2ccccc2)CNC(c2cc(-c3ccccc3)nc3ccccc23)=N1

Procedure:
2-Phenylbutane-1,2-diamine (328 mg, 2.0 mmol) in 4.4 mL of toluene is added dropwise to a stirred solution of trimethylaluminum (2.0 M, 1 mL) in 5 mL of toluene at below 10° C. under nitrogen. At the end of methane evolution, methyl-2-phenyl-4-quinolinecarboxylate (263 mg, 1 mmol) in 2 mL of toluene is gradually added at room temperature. The reaction mixture is refluxed for 3 hours under nitrogen. After cooling, the solution is treated with 1 mL of water, diluted with 1 mL of methanol and 1 mL of methylene chloride, and refluxed for 15 minutes. After separation of organic solvent and solvent evaporation, the residue is purified over silica gel chromatography eluting with 5-10% MeOH/CH2Cl2. The corresponding compound is obtained as a white solid.
Reaction SMILES: OS(O)(=O)=O.[CH:6]([C:9]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([CH:17]([CH3:19])[CH3:18])[C:10]=1N)([CH3:8])[CH3:7].N([O-])=O.[Na+].[I-:24].[K+]>CC#N.O>[I:24][C:10]1[C:9]([CH:6]([CH3:8])[CH3:7])=[CH:15][C:14]([Br:16])=[CH:13][C:12]=1[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1cc(Br)cc(C(C)C)c1I
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a 2 L 3-neck flask, equipped with mechanical stirrer, thermometer, and additional funnel, added 300 g of ice and 300 mL of H2SO4. 2,6-diisopropyl-4-bromoaniline (46.0 g, 0.18 mol) in 200 mL of CH3CN was added dropwise to this mixture while the temperature was maintained under 5° C. Then sodium nitrite (22.5 g, 0.32 mol) in 180 mL of ice cold water was added dropwise while the temperature was maintained around 0° C. The resulting clear solution was slowly poured into the solution of potassium iodide (105 g, 0.63 mol) in 300 ml of water at room temperature. The mixture was stirred for 1 h. After regular work up, the crude product was distilled at 170° C. under vacuum to afford 1-iodo-2,6-diisopropyl-4-bromobenzene (60 g) as light brown soft solid upon cooling.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH2:19][CH2:20][O:21][CH3:22])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH2:19][CH2:20][O:21][CH3:22])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COCCN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)nn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 43 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 305a (200 mg, 0.60 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (238 mg, 0.60 mmol), K3PO4 (254 mg, 1.2 mmol), sodium acetate (98 mg, 1.2 mmol) and Pd(dppf)Cl2 (22 mg, 0.030 mmol), and acetonitrile/water (8/0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane (30 mL) and water (20 mL). The water layer was extracted with dichloromethane (2×30 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 305b (169 mg, 43%) as a yellow solid. MS-ESI: [M+H]+ 655.9
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11].C(=O)([O-])[O-].[Ca+2]>C(NCC)C.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.[Cu]I>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[NH:7]2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Nc1cc(Cl)ccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCNCC
Product: Fc1ccc(-c2cc3ccc(Cl)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.5 %

Procedure:
A mixture of 5-chloro-2-iodoaniline (33.0 g, 0.13 mol) and 1-ethynyl-4-fluorobenzene (26.4 g, 0.22 mol) in diethylamine (400 mL) was degassed with bubbling nitrogen for 20 min., then tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.7 mmol) and copper (I) iodide (170 mg, 0.9 mmol) were added and the mixture was stirred at room temperature for 12 h. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water (2×), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in dimethylformamide (250 mL), calcium carbonate (13 g, 0.13 mol) and copper (I) iodide (12.4 g, 0.07 mol) were added and the mixture was stirred at 120° C. for 22 h. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water (2×) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with ether/hexane and the solid was collected and dried in vacuo to give the title compound (25.4 g, 85%). 1H NMR (360 MHz, CDCl3) δ 7.59 (2H, m), 7.49 (1H, d, J 8.5 Hz), 7.44 (1H, s), 7.24-6.99 (3H, m), and 6.69 (1H, d, J 1.8 Hz).