Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]=[CH:11]OC.[NH:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[NH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:11]=[N:15][NH:14][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: NNc1ccncc1
Reactant: COC=Cc1cc(OC)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COc1ccc(Br)c(CC=NNc2ccncc2)c1
Yield: 9.9 %

Procedure:
A mixture of 4-bromo-1-methoxy-3-(2-methoxyvinyl)benzene (42.3 g), 4-hydrazinopyridine (27.6 g), and p-toluenesulfonic acid (3.3 g) in ethanol (500 ml) was heated under reflux overnight, with stirring. The reaction mixture was filtered, and the filtrate was concentrated to about 50% of its initial volume. The precipitate was collected to give 5.5 g of product, as the hydrochloride salt, and the filtrate was concentrated. Saturated sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on a Waters LC2000 instrument, gradient eluting with: 1% ethylamine/2% methanol/97% ethyl acetate/1% triethylamine acid/5% methanol/94% ethyl acetate. The appropriate fractions were collected and concentrated to yield 4.9 g (8.8%) of product, mp 142° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>O1CCCC1>[CH2:3]([Si@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH3:1]
Reactant: Fc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1
Reactant: CCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)cc3)cc2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of tetrahydrofuran (hereafter abbreviated as "THF") to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.1 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-4-fluorobiphenyl to obtain 4'-(trans-4-n-propyl-4-silacyclohexyl)-4-fluorobiphenyl.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[CH:9]1([C:4]2[CH:5]=[C:6]([N:18]3[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1nc(Cl)cc(C2CCCC2)n1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(c2cc(C3CCCC3)nc(N)n2)CC1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A solution of crude 2-amino-4-chloro-6-cyclopentylpyrimidine (92 mg, 0.47 mmol), and N-methyl piperazine (0.15 mL, 1.4 mmol) in EtOH (2 mL) was heated at 70° C. for 2 h. The reaction was cooled to rt and concentrated and the crude residue chromatographed (2 M NH3 in MeOH/CH2Cl2) to yield an oil (81 mg, 66%). MS (ESI): mass calcd. for C14H23N5, 261.2; m/z found, 262.3 [M+H]+. 1H NMR (CDCl3): 5.85 (s, 1H), 4.78 (s, 2H), 3.59 (t, J=5.0, 4H), 2.81 (q, J=8.7, 1H), 2.44 (t, J=5.0, 4H), 2.32 (s, 3H), 2.04-1.89 (m, 2H), 1.82-1.59 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([O:15][CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:43][C@H:42]3[N:38]([CH2:39][CH2:40][CH2:41]3)[C:37]([CH3:45])([CH3:44])[CH2:36]2)[C:31]([C:46]#[N:47])=[CH:30][N:29]=1.[C:48]1([S:54]([OH:57])(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(O)C>[CH3:44][C:37]1([CH3:45])[CH2:36][C@H:35]([NH:34][C:32]2[C:31]([C:46]#[N:47])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:7]=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[C:5]([O:15][CH2:16][CH2:17][OH:18])=[CH:4][C:3]=3[F:26])[N:33]=2)[CH2:43][C@H:42]2[N:38]1[CH2:39][CH2:40][CH2:41]2.[C:48]1([S:54]([OH:57])(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Cn1nnn(-c2cc(N)c(F)cc2OCCO[Si](C)(C)C(C)(C)C)c1=O
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2C#N)C[C@@H]2CCCN21
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(C#N)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2OCCO)c1=O
Temperature: 80 °C

Procedure:
A mixture of 1-(5-amino-2-(2-(tert-butyldimethylsilyl)oxyethoxy)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (200 mg), (7R,8aS)-N-(2-chloro-5-cyanopyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (120 mg), and benzenesulfonic acid (120 mg) in IPA (2 mL) was heated to 80° C. overnight. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The crude product was absorbed onto silica gel and purified by CombiFlash chromatography (2N NH3 in MeOH/CH2Cl2=0-20%) to give desired product with benzenesulfonic acid. The methanol solution of the salt was passed through an ion-exchange resin column to remove acid to give the free base of compound 78 (120 mg, 57%).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:15][C:14]([CH3:16])=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[NH2:22][S:23]([CH2:26][C:27](O)=[O:28])(=[O:25])=[O:24].ON1C(=O)CCC1=O>>[NH2:22][S:23]([CH2:26][C:27]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:15][C:14]([CH3:16])=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:28])(=[O:25])=[O:24]
Reactant: NS(=O)(=O)CC(=O)O
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: O=C1CCC(=O)N1O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(N)(=O)=O)[C@H]3SC2)s1

Procedure:
Using the procedure of Example 3, 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid is reacted with N-hydroxysuccinimidyl aminosulfonylacetate (prepared in a similar manner as set forth in Example 1 from aminosulfonylacetic acid and N-hydroxysuccinimide) to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][C:22]([CH3:37])([CH3:36])[CH2:23][N:24]([CH3:35])[CH2:25][C:26]([N:29]1[CH:33]=[C:32]([NH2:34])[N:31]=[CH:30]1)([CH3:28])[CH3:27]>>[CH3:21][C:22]([CH3:37])([CH3:36])[CH2:23][N:24]([CH3:35])[CH2:25][C:26]([N:29]1[CH:33]=[C:32]([NH:34][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:31]=[CH:30]1)([CH3:27])[CH3:28]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CN(CC(C)(C)C)CC(C)(C)n1cnc(N)c1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN(C)CC(C)(C)C)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-{2-[(2,2-Dimethyl-propyl)-methyl-amino]-1,1-dimethyl-ethyl}-1H-imidazol-4-ylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 26.8, 28.2, 28.8, 28.9, 29.8, 33.4, 36.6, 46.6, 52.8, 59.4, 59.5, 60.9, 72.4, 74.2, 101.1, 104.8, 106.9, 110.7, 110.9, 118.0, 131.1, 137.4, 139.3, 139.8, 162.2, 172.4, 194.6; MS m/z 504.4 (M+1).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>CCO>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][N:21]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: NCC(O)CO
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(CC(O)CO)cc2n(C)c1=O

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C)(670 mg, 1.987 mmol), 3-aminopropane-1,2-diol (0.231 ml, 2.98 mmol) and TEA (0.554 ml, 3.97 mmol) were combined in EtOH (15 ml) and heated at reflux for 15 mins.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([C:26]([F:29])([F:28])[F:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1.CO.[Ni]>[CH2:1]([NH:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[C:11]([C:26]([F:29])([F:28])[F:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1NCc1ccccc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(NCc2ccccc2)cc(C(F)(F)F)nc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
N2,N4-Dibenzyl-3-nitro-6-trifluoromethyl-pyridine-2,4-diamine (15.9 g, 35.6 mmol) was dissolved in a mixture of THF (100 ml) and MeOH (200 ml). Raney Nickel (3.18 g, 20 wt %) was added and the mixture was stirred at room temperature under 80 psi H2 for 1 hour. The mixture was filtered through celite to remove the catalyst and the filtrate was concentrated in vacuo to give an oil. Trituration in MeOH with a small amount of water gave a precipitate which was collected by filtration, washed with cold MeOH and dried in vacuo to give the title compound (9.02 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][CH2:27][O:26][C:25]3=[O:29])=[CH:20][C:19]=2[S:30]([CH3:33])(=[O:32])=[O:31])=[O:17])[CH2:12][CH2:11]1.[CH3:34]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[F:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH3:34])=[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][CH2:27][O:26][C:25]4=[O:29])=[CH:20][C:19]=3[S:30]([CH3:33])(=[O:32])=[O:31])=[O:17])[CH2:12][CH2:11]2)[CH:4]=1
Reactant: Cc1cc(Cl)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3S(C)(=O)=O)CC2)cc1F
Reactant: CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3S(C)(=O)=O)CC2)cc1F
Yield: 11.5 %

Procedure:
To a mixture of 3-{4-[4-(2-chloro-5-fluoro-4-methylphenyl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}oxazolidin-2-one (0.5 g) described in Preparation Example 14, methylboronic acid (479 mg), palladium (II) acetate (90 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (328 mg) and potassium fluoride (930 mg) was added tetrahydrofuran (12 mL), and the mixture was refluxed for 18 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (55 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[NH2:17][CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:17][CH2:18][C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccco1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccco3)c3ccccc3nc21
Yield: 34.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 0.0043 mol), DMSO (3 mL) and 2-aminomethylfuran (0.8 mL, 0.009 mol) was heated at 90° for 3 hours. The reaction mixture was then partitioned between CH2Cl2 (50 mL) and water (50 mL). The aqueous layer was separated and then extracted with CH2Cl2 (25 mL) and then the CH2Cl2 layers were combined, washed with water dried over Na2SO4 and reduced to a volume of about 3-5 mL. The solution was passed through a silica gel column eluting with ethyl acetate to afford the product which was recrystallized from ether/CH2Cl2 to afford 430 mg of 1-ethyl-N-(2-furanylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 156°-158° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH:9]=[CH:8][S:7][CH:6]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].S(Cl)(Cl)(=O)=O>>[C:1]([NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1C=CSC1C(=O)c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)Nc1ccsc1C(=O)c1ccccc1
Yield: 82 %

Procedure:
Using the method described in Example 14(c), 2.47 parts of 3-acetylamino-2-benzoyldihydrothiophene, on reaction with 0.66 parts of sulfuryl chloride for one hour at 0° C., give 2.0 parts of 3-acetylamino-2-benzoylthiophen (82% of theory) of melting point 93°-95° C.
Reaction SMILES: CO[C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4].CCN(CC)CC.[Cl:19][CH2:20][C:21]([NH2:23])=[NH:22].C(Cl)Cl>CO>[Cl:19][CH2:20][C:21]1[NH:23][C:3](=[O:4])[C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:10]=2[N:22]=1
Reactant: COC(=O)C1COCCC1=O
Reactant: N=C(N)CCl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c(CCl)nc2c1COCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A mixture of crude 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester (1780 g, 11 mol) and NEt3 (830 g, 8.2 mol) in MeOH (3560 mL) was cooled to 0° C. under N2. A solution of 2-chloro-acetamidine (567 g, 4.4 mol) in 890 mL of MeOH was added dropwise over 50 minutes. The reaction mixture was stirred at 0° C. for 30 minutes and then at about 20° C. for 16 hours. LCMS at 215 nm and TLC (DCM:MeOH=10:1) analysis showed that most of 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester was consumed. The mixture was then filtered and concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel and eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (1200 mL) and H2O: CH3CN: EA=1:1:2 (˜600 mL) to give the title compound as a white solid (318 g). MS m/z 201.2 (M+H). CHN analysis: calculated (results). C, 47.89 (47.95), H, 4.52 (4.401), N, 13.96 (13.76).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C1COCC1.[Pd]>[CH:1]1([CH2:7][NH:8][C:9]2[C:14]([NH2:15])=[CH:13][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CN1CCN(c2cc(NCC3CCCCC3)c([N+](=O)[O-])cc2Nc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(NCC3CCCCC3)c(N)cc2Nc2ccccc2)CC1
Reaction time: 0.05 h
Yield: 47.9 %

Procedure:
To a solution of N4-cyclohexylmethyl-2-(4-methyl-piperazin-1-yl)-5-nitro-N1-phenyl-benzene-1,4-diamine (0.22 g, 0.53 mmol) in THF (5.00 mL) was added 10% palladium on activated carbon (0.22 g). The reaction flask was equipped with a septum and was placed under vacuum for 3 min. This flask was placed under hydrogen atmosphere (balloon inflated with hydrogen) and the reaction mixture was stirred for 18 h. The palladium was filtered off through a plug of diatomaceous earth and washed with EtOAc. The solvent was removed via rotary evaporation. The resulting residue was flash chromatographed (5% MeOH/CH2Cl2), yielding N1-cyclohexylmethyl-5-(4-methyl-piperazin-1-yl)-N4-phenyl-benzene-1,2,4-triamine (0.10 g, 49.5% yield). M+, 392
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:46]CC2C=CC=CC=2)[C@H:15]([N:31](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:54][CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:9]1[CH3:60])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(C)(C)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:46])[C@@H:15]([NH2:31])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:54][CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:9]1[CH3:60])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](OCc2ccccc2)[C@@H](Cc2cccc(OCc3ccccc3)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](O)[C@@H](N)Cc2cccc(O)c2)N1C(=O)OC(C)(C)C
Yield: 104.2 %

Procedure:
Dissolve 5-(R)-[1-(S)-benzyloxy-3-(3-benzyloxyphenyl)-2-(R)-dibenzylaminopropyl]-2-(R)-(2,2-dimethylpropoxy)-3-(S)-methylmorpholine-4-carboxylic acid tert-butyl ester (1.38 g, 1.70 mmol) in tert-butanol (˜50 mL). Add 20% palladium hydroxide on carbon (4 g) and hydrogenate at 50 psi hydrogen gas at 40° C. for 18 hours. Filter and concentrate to give the desired compound (802 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.O>CN(C=O)C>[CH3:8][C:3]1[C:2]([O:1][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ncccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
3-Hydroxy-2-methylpyridine (40 g, 0.37 mole) in dry DMF (1.3 L) under argon was cooled to 0° C. Sodium hydride (11.1 g of an 80% dispersion in oil, 0.37 mole) was added portionwise and the mixture stirred at 0° C. for 15 minutes and then room temperature for 3 hours. 2-Chloro-5-nitropyridine (58.6 g, 0.37 mole) was added and the mixture stirred for 18 hours at r.t. Water (50 ml) was added dropwise and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with 10% aqueous sodium hydroxide, and water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (81.1 g, 95%) as a yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20](=[O:22])=[O:21]>C1COCC1>[Cl:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: O=C=O
Reactant: Clc1ccncc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
4-Chloropyridine hydrochloride (25 g) is neutralized with aq. Na2CO3 (10%) and extracted with DCM. The organic layer is separated, dried over Na2SO4 and concentrated under reduced pressure to afford 4-chloropyridine (19 g). To a solution of diisopropylamine (31 mL, 217.6 mmol) in dry THF is added n-butyllithium (115 mL, 184.1 mmol) dropwise at −78° C. under nitrogen. After 30 min, a solution of 4-chloropyridine (19 g, 167.4 mmol) in dry THF is slowly added under nitrogen. The reaction mixture is further stirred for 1 h at −78° C. before addition of solid CO2, let warmed to RT and stirred at RT for 12 h under nitrogen. After this time, reaction mixture is concentrated under reduced pressure and acidified with aq. HC1 solution (1.5 N) under ice-cooled condition. Precipitate is filtered under reduced pressure and dried overnight under vacuum to afford 15 g (57%) of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 6 13.83 (bs, 1H), 8.92 (s, 1H), 8.64-8.63 (d, J=5.4 Hz, 1H), 7.66-7.65 (d, J=5.4 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1CCOC.[F:24][C:25]1[CH:30]=[C:29]([CH:31]([CH3:35])[C:32](Cl)=[O:33])[CH:28]=[CH:27][C:26]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[CH:31]([C:29]3[CH:28]=[CH:27][C:26]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[C:25]([F:24])[CH:30]=3)[CH3:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CC(C(=O)Cl)c1ccc(-c2ccccc2)c(F)c1
Product: CC(C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21)c1ccc(-c2ccccc2)c(F)c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-(2-fluoro-4-biphenylyl)propionyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(2-fluoro-4-biphenylyl)propanamide as a white powder, m.p. 76.1-79.9° C. 1H NMR (300 MHz, DMSO-d6) δ8.17 (s, 1H), 8.03 (m, 2H), 7.62 (d, J=8.3 Hz, 1H), 7.49-7.14 (m, 10H), 6.59 (broad s, 2H), 4.58 (t, J=6.9 Hz, 2H), 3.59 (q, J=7.0 Hz, 1H), 3.09 (pentet, J=6.7 Hz, 2H), 1.82 (m, 2H), 1.45 (m, 2H), 1.30 (d, J=7.0 Hz, 3H); MS (EI) m/e 481.2268 (481.2278 calcd for C29H28FN5O).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:8].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[C:24]=1[Cl:32]>C1COCC1>[C:18]([C:4]1[NH:3][C:2]([NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[C:24]=2[Cl:32])=[O:31])=[C:6]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]2([CH3:16])[CH3:17])=[O:8])[CH:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1cc(C(=O)N2CCNC(=O)C2(C)C)c(N)[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)N2CCNC(=O)C2(C)C)c(NC(=O)Nc2cccc(Cl)c2Cl)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To 4-(2-amino-5-tert-butyl-1H-pyrrole-3-carbonyl)-3,3-dimethyl-piperazin-2-one 7 (60 mg, 0.21 mmol) in THF (1 mL) was added 1,2-dichloro-3-isocyanatobenzene (58 mg, 0.31 mmol) in THF (1 mL). The resulting reaction mixture was stirred at room temperature for 1 h, at which time, TLC indicated the completion of the reaction. The solvent was then removed in vacuo, and the residue was purified by prep. TLC (EtOAc/MeOH: 9.5/0.5) to provide 1-(5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)-1H-pyrrol-2-yl)-3-(2,3-dichlorophenyl)urea (14.6 mg, 15%) as off-white solid. 1H NMR (400 MHz, CD3OD): δ (ppm) 7.93 (t, J=4.9 Hz, 1H), 7.20 (q, J=1.9 Hz, 2H), 5.68 (s, 1H), 3.87 (t, J=5.1 Hz, 2H), 3.44 (t, J=5.0 Hz, 2H), 1.75 (s, 6H), 1.25 (s, 9H).
Reaction SMILES: C[C@@H](O)[C@H](O)/C(/C)=[CH:5]/[CH2:6][CH:7](/[CH:9]=[C:10]1/[CH2:11][C@@:12]([OH:20])(C)[C@H]2N(C/1)CCC2)C.C1C=C[C:27]([CH2:30][O:31]CCC#N)=[CH:26]C=1.C(#N)C=C.C(O)C1C=CC=CC=1.[AlH](CC(C)C)CC(C)C>>[CH2:12]([O:20][CH2:26][CH2:27][CH:30]=[O:31])[C:11]1[CH:5]=[CH:6][CH:7]=[CH:9][CH:10]=1
Reactant: N#CCCOCc1ccccc1
Reactant: C/C(=C\CC(C)/C=C1\CN2CCC[C@H]2[C@@](C)(O)C1)[C@@H](O)[C@@H](C)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C=CC#N
Solvent: OCc1ccccc1
Product: O=CCCOCc1ccccc1

Procedure:
To generate indolizidine alcohol and aldehyde intermediates useful in the synthesis of pumiliotoxin B, it is necessary to assemble a chiral silylalkyne from esters of (S)-5-(benzyloxy)-1-trimethyl-silyl-1-pentyn-3-ol. This involves the reduction of 3-(benzyloxy)propanitrile, the latter reagent being prepared from acrylonitrile and benzyl alcohol as described by Gaiffe and Launay in Academy of Science, Serial C, Pages 1379-1380 (1968), with i-Bu2AlH to give 3-benzyloxy propanal which is condensed with ethynyllithium, prepared as described by Midland in the Journal of Organic Chemistry, Volume 40, Page 2250 (1975), to yield the racemic propargylic alcohol in about 50% yield following distillation. Reaction of the propargylic alcohol with R-(+)-2-methylbenzylamine gives the corresponding diastereomeric carbamates that upon chromatographic separation and carbamate cleavage with Cl3SiH as described by Pirkle in the Journal of Organic Chemistry, Volume 42, Page 2781 (1971) yields the (S)-alcohol and (R)-alcohol derivatives in yields of about 20%.