Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:45]([NH:47][C@H:48]([C:53](O)=[O:54])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([O:24][C:53]([C@@H:48]([NH:47][CH:45]=[O:46])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:54])[CH2:11][C@@H:10]1[O:9][C:8](=[O:25])[C@H:7]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)C[C@H](NC=O)C(=O)O
Reactant: CCCCCCCCCCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(C)C)NC=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
166 g of (3S,4S)-3-hexyl-4-((R)-2-hydroxy tridecyl)-2-oxetanone obtained from Reference Example 1 was dissolved in 830 mL of tetrahydrofuran. After the addition of 160 g of triphenylphosphine (PPh3) and 86 g of N-formyl-L-leucine, the reaction mixture was cooled to 0° C. A mixed solution where 120 mL of diisopropylazodicarboxylate (DIAD) was diluted in 332 mL of tetrahydrofuran, was continuously added thereto over 1.5 hours. After stirring for further 30 minutes, the reaction mixture was stirred for 4 hours while slowly raising its temperature. After removing the solvent, 832 mL of hexane was added thereto, and the reaction mixture was stirred for 5 hours. The formed solid was removed therefrom by filtration, and the hexane layer thereof was washed with 499 mL of 55% methanol/distilled water three times. The remaining organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was removed under a reduced pressure. Then, 2.5 L of hexane was added thereto, and the reaction mixture was cooled to 10° C. and stirred for 1 hour, followed by addition of a seed of orlistat solid. The reaction mixture was slowly cooled to 0° C. again, and stirred overnight. The obtained solid was filtered, washed with 500 mL of cold hexane, and dried, to obtain 192.5 g of the title compound (yield: 83%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][C@H]2C(C)(C)COC2=O)=[O:9])[CH2:4][CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH:3]=1
Reactant: CC1=CC[C@H](C(=O)O[C@@H]2C(=O)OCC2(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1=CC[C@H](C(=O)O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
(R)—((S)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl) 4-methylcyclohex-3-enecarboxylate 502 (1.30 g, 5.15 mmol) in THF (10 mL), water (1 mL) and methanol (1 mL) was treated with lithium hydroxide monohydrate (2.16 g, 51.5 mmol) and warmed to 50° C. with stirring. After 1 hour, the reaction mixture treated with 1M HCl. The mixture was extracted with hexanes:THF (10:1), dried over sodium sulfate, filtered and concentrated to 0.738 g (quantitative yield) of (R)-4-methylcyclohex-3-enecarboxylic acid 503 as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#N.[C:9](#N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:9]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccnc1
Reactant: N#Cc1ccccc1
Product: C(#Cc1cccnc1)c1ccccc1
Reaction time: 20 h
Yield: 45 %

Procedure:
The procedure was identical to Example 2, with the exception that 3-cyanopyridine (0.208 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 0.89 mmol (45% yield) of 3-(phenylethynyl)pyridine and no remaining 3-cyanopyridine in the reaction mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])OC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.O>C1(C)C=CC=CC=1.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCc1cccnc1
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
11.77 g (0.06 mole) of methyl N-(4-nitrophenyl)carbamate, 5.4 g (0.05 mole) of 3-aminomethyl-pyridine, 18.7 g (0.065 mole) of Genamin SH 302 D (a mixture of N,N-dimethyl-C16-18 alkylamines sold by the firm Hoechst AG) and 200 ml of toluene are introduced into the apparatus described in Example 4, and the mixture is boiled for 4 hours. During this period 15 ml of a mixture of water, methanol and toluene accumulate in the trap. The separated solid is filtered off, washed twice with 10 ml of hot toluene, and the resulting mixture is used as reaction medium in the above reaction. The mother liquor is recycled 10 times. The results of the individual cycles are summarized in Table 1.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[CH2:3]1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
To a stirred solution of 3-oxocyclopentanecarboxylic acid (1.5 g, 11.71 mmol) in DMF (20 mL) was added K2CO3 (1.780 g, 12.88 mmol) followed by benzyl bromide (1.360 mL, 11.71 mmol) under nitrogen. The reaction mixture was then stirred for 18 h at RT. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 332A (2.1 g, 78% yield) as an oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.42-7.31 (m, 5H), 5.16 (s, 2H), 3.22-3.12 (m, 1H), 2.58-2.45 (m, 2H), 2.44-2.29 (m, 2H), 2.23 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([NH:16][NH2:17])=[N:7][CH:6]=1
Reactant: NN
Reactant: Clc1ncc(-c2ccccc2Cl)nn1
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccccc2Cl)nn1

Procedure:
A solution of 19.8 g. of 3-chloro-6-(o-chlorophenyl)-1,2,4-triazine in 120 ml. of pyridine is treated with 15 g. of hydrazine hydrate as described in Example 12, giving 6-(o-chlorophenyl)-3-hydrazino-1,2,4-triazine as yellow needles.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32].O>CO>[OH:32][CH2:31][C@@H:30]([NH:29][C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:9]=1)=[O:28])[CH3:33]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Reactant: C[C@H](N)CO
Solvent: O
Solvent: CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@@H](C)CO)cc2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester (1.8 g) and (S)-(+)-2-amino-1-propanol (0.71 g) were dissolved in methanol (30 ml) and heated to reflux for 12 hours. The reaction mixture was cooled and with the slow addition of excess of water at 40° C. to precipitate the crystals, the mixture was cooled again and stirred at 20° C. for 1 hour. Following with filtration and washing with water, the filtered solid was recrystallized using isopropanol and ether, filtered and dried to give 1.66 g (yield: 83%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][C:21](=[O:23])[CH3:22])[C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine (2.29 g, 0.01 mole), was added to a suspension of sodium hydride (0.44 g of 60% sodium hydride/oil, 0.01 mole, washed once with hexanes) in 50 ml of dimethylformamide. The mixture was heated to 70° C. for 1 hr before the addition of chloroacetone (0.93 g, 0.01 mole) at room temperature. The reaction mixture was stirred at room temperature overnight, then poured into 300 ml of water. The precipitate was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight. The solid was recrystallized from methanol-water and dried under high vacuum at 50° C. overnight. The solid was dissolved in methanol, treated with charcoal, and filtered through Celite to give a pale yellow filtrate. The filtrate was concentrated and diluted with water to initiate crystallization. The precipitate was collected by filtration, washed with water, and dried under high vacuum overnight. The solid was dissolved in isopropyl alcohol, acidified with ethereal hydrogen chloride, diluted with isopropyl ether, and seeded to initiate crystallization. The crystalline solid was collected by filtration, washed with isopropyl ether, and dried under high vacuum overnight to give 1.6 g (50%), m.p. 220°-22° C.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[O:9]1[C:11]2[CH2:12][CH2:13][CH2:14][C:10]1=2.O1CCCC1>[Pd].CS(C)=O>[OH:9][CH:10]1[CH2:14][CH:13]([N:1]2[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[CH:12]=[CH:11]1
Reactant: C1CC2=C(C1)O2
Reactant: Nc1cc[nH]c(=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Nc1ccn(C2C=CC(O)C2)c(=O)n1
Temperature: 25 °C
Reaction time: 90 h
Yield: 79.1 %

Procedure:
52.5 g (0.47 mol) of cytosine are reacted with 38.5 g (0.47 mol) of epoxycyclopentene at 0° C., by slow addition, in a mixture of in each case 220 ml of dry tetrahydrofuran and dimethylsulfoxide with 1 mol % of the palladium(0) catalyst prepared in situ as described above under an inert argon atmosphere. The reaction mixture is stirred at room temperature for 90 hours and then freed from the solvent and the residue is chromatographed over silica gel using methylene chloride/methanol 7/3. 71.8 g (79.2% of theory) of 1-[(1RS,4SR)-4-hydroxycyclopent-2-en-1-yl]cytosine of melting point 241°-242° C. are obtained. 1H-NMR (270 MHz, d6 -DMSO), δ[ppm]: 7.42 (d, 1H), 7.02 (s, 2H), 6.09 (m, 1H), 5.75 (m, 1H), 5.72 (d, 1H), 5.44 (m, 1H), 5.18 (d, 1H), 4.63 (m, 1H), 2.72 (m, 1H), 1.27 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([C:20]1([NH2:43])[C:26](=[O:27])[N:25]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:21]1=[O:42])=[O:19])[CH3:17]>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([C:20]2([NH2:43])[C:26](=[O:27])[N:25]([CH2:28][C:29]([CH3:32])([CH3:30])[CH3:31])[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[N:22]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:21]2=[O:42])=[O:19])[CH3:17])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Agent: Cl
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluoromandelic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white solid (melting point=116-126° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.54 and 0.40 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.C(S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O)(F)(F)F.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH:20][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: NC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: FC(F)(F)CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a 50 mL round-bottom flask containing a solution of 1-N-[7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (288 mg, 1.00 mmol, 1.00 equiv) in DMF (10 mL) was added F3CSO3CH2CF3 (700 mg, 3.02 mmol, 3.00 equiv) and DBU (457 mg, 3.01 mmol, 3.00 equiv) in ice-water bath under nitrogen. The resulting solution was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled down to room temperature and then quenched with water, diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (30:1 to 20:1) to provide the desired 1-N-[7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-4-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (300 mg, 81%) as a white solid. MS (electrospray) m/z 371 (M+H)+; 1H NMR (400 MHz, CD3OD): 8.22 (s, 1H), 4.06-4.14 (m, 1H), 3.24-3.32 (q, 2H), 3.01 (t, 2H), 3.07 (t, 2H), 2.51-2.78 (m, 3H), 2.04-2.15 (m, 4H), 1.43-1.55 (m, 2H), 1.28-1.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:24]3[C:11]([CH2:12][C:13]4[C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[N:15]([CH3:22])[C:14]=4[CH2:23]3)=[C:10]([C:25](OC)=[O:26])[C:9]=2[C:29](OC)=[O:30])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:24]3[C:11]([CH2:12][C:13]4[C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[N:15]([CH3:22])[C:14]=4[CH2:23]3)=[C:10]([CH2:25][OH:26])[C:9]=2[CH2:29][OH:30])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(Cl)cc2)n2c1Cc1c(n(C)c3ccccc13)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c2c(c3ccccc31)Cc1c(CO)c(CO)c(-c3ccc(Cl)cc3)n1C2
Reaction time: 0.25 h

Procedure:
A solution of dimethyl 3-(4-chlorophenyl)-6-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate (3.2 g, 7 mmol) in anhydrous dichloromethane (35 mL) was added dropwise into a stirred suspension of LiAlH4 (0.6 g, 17.8 mmol) in anhydrous diethyl ether (20 mL) at 0 to −5° C. The reaction mixture was further stirred for 15 min after the addition was completed. The excess hydride was destroyed by the sequential addition of water (1 mL), 15% aqueous NaOH (1 mL), and water (1 mL) at 0° C. The mixture was filtered through a pad of Celite and the solid was washed with dichloromethane. The combined filtrate and washings were evaporated to dryness in vacuo. The residue was triturated with ether to give (3-(4-chlorophenyl)-6-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-diyl)-dimethanol (BO-1934), 2.2 g (77%); mp 238-239° C. 1H NMR (DMSO-d6) δ 3.62 (3H, s, Me), 4.10 (2H, s, CH2), 4.29 (2H, m, CH2), 4.55 (2H, s, CH2) 4.59 (2H, brs, exchangeable, 2×OH), 5.16 (2H, s, CH2), 7.04-7.08 (1H, m, ArH), 7.14-7.18 (1H, m, ArH), 7.43-7.45 (1H, m, ArH), 7.53-7.59 (5H, m, 5×ArH). Anal. Calcd for (C23H21ClN2O2.0.5H2O): C, 68.74; H, 5.52; N, 6.97. Found: C, 68.72; H, 5.16; N, 6.94.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[O:14][CH2:13]1>>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=3[CH3:1])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Product: Cc1c(NCc2ccc3c(c2)OCO3)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitroaniline and 1,3-benzodioxole-5-carbaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[Si](C=[N+:15]=[N-:16])(C)(C)C>C(Cl)Cl.CO>[C:1]([NH:15][NH2:16])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: C=CCCCCC(=O)NN
Reaction time: 0.5 h

Procedure:
To a solution of 6-heptenoic acid (1.24 g, 9.68 mmol) in methylene chloride (40 mL) and MeOH (10 mL) was added slowly TMSCHN2 (2M, 12.1 mL) at room temperature. The reaction mixture was stirred for additional 30 minutes. After the reaction was completed, the mixture was evaporated in vacuo. The residue was directly used for the next step without further purification. To the above residue in MeOH (20 mL) was added hydrazine monohydrate (5 mL) at room temperature. The reaction mixture was stirred at the same temperature overnight. The mixture was evaporated in vacuo. The residue was further dried by high vacuum overnight to provide the title compound. MH+143.
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.N(CC)(CC)CC.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][N:6]1[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]1
Reactant: COC(=O)CBr
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CN1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
Treat a ° C. solution of 4,4-difluoropiperidin HCl (17.91 g, 0.113 mol) and (CH3CH2)3N (28.75 g, 0.284 mol) in CH2Cl2 (250 mL) with methyl bromoacetate (17.37 g, 0.113 mol), warm to room temperature, and stir 16 hours at room temperature under N2. Dilute the reaction with saturated NaHCO3 and water and extract twice with 3:1 chloroform:isopropanol. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with 0 to 5% methanol in CH2Cl2 to afford 14.22 g (65%) of the titled product. Rf=0.77 (9/1 CH2Cl2/methanol). ES MS (m/z): 194 (M+).
Reaction SMILES: C[C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15](C)(C)[C:3]=1[C@@H:4]([O:59]C(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O.C(O)(=O)C.[Cl:67]CCl>C(OCC)(=O)C>[C:4]([Cl:67])(=[O:59])[C:3]1[CH:15]=[CH:14][CH:18]=[CH:19][CH:2]=1
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Cl)c1ccccc1

Procedure:
Before the C-4 sidechain can be added to the C-7 Cbz protected paclitaxel analog (9), the analog (9) must undergo protection of the 2-OH. The protection step is carried out by treating the reaction mixture containing analog (9) with an acid, preferably acetic acid to neutralize the reaction mixture. The dichloromethane in the neutralized reaction mixture is exchanged for ethyl acetate or other ester or amide organic solvent, and the resulting solution of 9 is treated with a strong base, preferably Li t-butoxide, and a benzoyl protecting agent, preferably benzoyl chloride, to form the 2-benzoyl (Bz) 7-hydroxy protected paclitaxel (10).
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH3:17])[C:6]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C.C[O-].[Na+]>C1COCC1.CO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([OH:4])=[C:6]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:7]([CH3:17])=[CH:8]2
Reactant: COc1ccc2c(OC(C)=O)c(-c3ccccc3)c(C)cc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of 3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl acetate (6) (4.00 g, 13.1 mmol) in THF and MeOH (200 mL, 1:1) was added sodium methoxide (26 mL, 0.5 M solution in MeOH) at room temperature. The reaction mixture was stirred for 3 h under N2. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by SiO2 column chromatography to afford 3.4 g (99%) of compound 7 as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J=8.0 Hz, 1H), 7.54 (dd, J1=12.0 Hz, J2=8.0 Hz, 2H), 7.45 (dd, J1=8.0 Hz, J2=8.0 Hz, 1H), 7.36 (d, J1=4.0 Hz, 2H), 7.23 (s, 1H), 7.10 and 7.08 (dd, J1=8.0 Hz, J2=4.0 Hz, 1H), 7.05 (d, J1=4.0 Hz, 1H), 5.21 (s, 1H), 3.93 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[N:16]1([C:22]2[CH:27]=[C:26]([C:28](=[O:30])[CH3:29])[CH:25]=[CH:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[C:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([N:16]2[CH2:17][CH2:18][N:19]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:20][CH2:21]2)[CH:27]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1ccnc(N2CCNCC2)c1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccnc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (34 mg, 0.24 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (21 μl, 0.24 mmol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of 1-(2-piperazin-1-yl-4-pyridyl)ethanone (41 mg, 0.2 mmol) and DIPEA (105 μl, 0.6 mmol) in anhydrous DCM (2 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 37 mg of a solid (0.108 mmol, yield 47%).