Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3C(=CC=CC=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[C@H]2[C@@H](O)C[N:36]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])C2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@H:11]2[C@@H:12]([OH:20])[CH2:13][N:36]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:19]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Product: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.38, 5.16, 4.91, 4.82, 4.59, 4.48, 4.59, 4.48, 4.01, 3.72-3.58, 3.36-3.25, 2.81, 2.69, 2.54, 2.46, 1.31-1.23.
Reaction SMILES: [N:1]1([CH:6]2[CH2:20][C:9]3[C:10]4[NH:11][C:12](=[O:19])[C:13](=[O:18])[NH:14][C:15]=4[CH:16]=[CH:17][C:8]=3[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:21]([O-])([OH:23])=[O:22]>FC(F)(F)C(O)=O>[N+:21]([C:17]1[C:8]2[CH2:7][CH:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:20][C:9]=2[C:10]2[NH:11][C:12](=[O:19])[C:13](=[O:18])[NH:14][C:15]=2[CH:16]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccc3c(c2[nH]c1=O)CC(N1CCCC1)C3
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CC(N1CCCC1)C3

Procedure:
Nitration of 8-pyrrolidin-1-yl-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione as described before with fuming nitric acid in trifluoroacetic acid gave the product as a yellow solid (0.1 g). C15H16N4 O4.HCL. MS M+1 (317). HPLC 99%.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[N:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:27]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 11A for the product of Example 1E and substituting 5-methyl-2(1H)-pyridone for 3(2H)-pyridazinone. 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (d, J=8.42 Hz, 1H) 7.88 (d, J=2.18 Hz, 1H) 7.42 (dd, J=8.58, 2.03 Hz, 1H) 7.28 (dd, J=9.36, 2.50 Hz, 1H) 7.15 (s, 1H) 6.62 (d, J=9.36 Hz, 1H) 3.59-3.69 (m, 1H) 3.15-3.25 (m, 1H) 3.01-3.10 (m, 1H) 2.77-2.85 (m, 1H) 2.60-2.67 (m, 1H) 2.33-2.56 (m, 3H) 2.12 (s, 3H) 1.93-2.03 (m, 1H) 1.79-1.88 (m, 1H) 1.68-1.77 (m, 1H) 1.45-1.64 (m, 2H) 1.16 (s, 3H). MS: (M+H)+=380.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].[P:38]([O:45]CC)([O:42]CC)[O:39]CC>>[P:38]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])([OH:45])([OH:42])=[O:39]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCBr
Product: O=P(O)(O)CCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 150 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
A mixture of 5.23 g of 1-bromo-11-(heptadecafluorooctyl)undecane and 4.2 g of triethyl phosphite was heated at 150° C. After 18 hr, diethyl ethylphosphonate and other volatiles were distilled from the reaction mixture, b.p. 30-50° C. at 0.05 torr (7 Pa). The concentrate was combined with an additional 2.0 g of triethyl phosphite, and the mixture was heated at 150° C. After 3 hr, volatiles were again distilled, and the crude 1-diethylphosphono-11-(heptadecafluorooctyl)undecane was dissolved in 10 mL of dichloromethane. To this solution was added 3.1 g of bromotrimethylsilane. After 18 hr at room temperature, the solution was concentrated to a nearly colorless liquid, and the intermediate silylphosphonate ester was dissolved in 200 mL of methanol. The resultant solution was stirred at room temperature for 3 hr and cooled to 0° C. The crude product was collected by filtration, and recrystallization from methanol afforded 2.32 g of 1-phosphono-11-(heptadecafluorooctyl)undecane (CF3(CF2)7 (CH2)11PO3H2) as white crystals, m.p. 115-117° C.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)[CH3:7])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:26]([O:33][C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C@H:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42](O)=[O:43])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O.O1CCOCC1>[CH2:26]([O:33][C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C@H:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42]([NH:1][C@@H:2]([C@H:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)[CH3:7])[C:3]([OH:5])=[O:4])=[O:43])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(N[C@@H](Cc1c[nH]cn1)C(=O)O)C(N)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@@H](N[C@@H](Cc1c[nH]cn1)C(=O)O)[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a mixture of 2S,3R)-2-amino-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (400 mg) and triethylamine (0.70 ml) in a mixture of water (10 ml) and dioxane (10 ml) was added (2S)-6-benzyloxycarbonylamino-2-t-butoxycarbonylaminohexanoic acid (894 mg) at 5° C. and the mixture was stirred in an ice-bath for 3 hours. The volatile solvent was evaporated in vacuo and the residue was adjusted to pH 4 with 1N hydrochloric acid. The mixture was subjected to a column of "Diaion HP-20" (80 ml). After the column was washed with water, the elution was carried out with a mixture of methanol and water (3:7-8:2) and the object fractions were collected and evaporated in vacuo. The residue was solidified with a mixture of methanol and ether to give (2S,3R)-2-[[(2S)-6-benzyloxycarbonylamino-2-t-butoxycarbonylaminohexanoyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (786 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1)CCC>>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:7][C:6]=1[C:8]1[N:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1cccnc1-c1cc(Br)ccc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: N#Cc1cccnc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
2-(5-Bromo-2-fluorophenyl)nicotinonitrile (214 mg, 0.8 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.1 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from toluene, gave 2-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]nicotinonitrile as a yellow solid: δH (400 MHz, CDCl3) 8.95 (1H, dd, J 5 and 2), 8.91 (1H, d, J 7), 8.17 (1H, dd, J 8 and 2), 8.13 (1H, s), 7.80 (1H, dd, J 7 and 2), 7.69-7.73 (1H, m), 7.46-7.55 (2H, m), 7.29 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12]O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(CCCO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CCCBr)c1
Reaction time: 12 h
Yield: 94.5 %

Procedure:
Compound 95-1 (220 mg) was dissolved in methylene chloride (10 ml), triphenylphosphine (350 mg) and N-bromosuccinimide (238 mg) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (30 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (280 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1>C1COCC1>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:22][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH3:21])=[N:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(F)c(F)nc1F
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of 2,3,6-trifluoro-5-nitropyridine (Method 56, 2.0 g, 11.2 mmol) in THF (50 ml) was cooled to 0° C., to which was added (S)-1-(4-fluorophenyl)ethanamine (1.56 g, 11.2 mmol). The reaction was stirred at 0° C. for 30 min., then quenched with water (50 ml) and extracted with DCM (2×75 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (hexanes-DCM=1:1) to give the title compound (2.3 g, 70%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:11](Br)[C:12]#[CH:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:13]([N:6]1[CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:4][CH2:5]1)[C:12]#[CH:11]
Reactant: FC(F)(F)C1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#CCN1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
4-Trifluoromethylpiperidine (2.0 g, 13 mmol) was added to a solution of propargyl bromide (80 wt. % 5.4 g, 36 mmol) in ethanol (30 ml). Potassium carbonate (5.4 g, 39 mmol) was added and the mixture was stirred at room temperature for 20 hours. The mixture was filtered and the solids washed with ethyl acetate. The filtrate was evaporated in vacuo, diluted with sodium hydrogen carbonate (sat, 50 ml) and extracted with ethyl acetate (2×40 ml). The extracts were washed with brine, dried (MgSO4) and evaporated in vacuo to provide 1-propargyl-4-trifluoromethylpiperidine as a brown oil (795 mg, 32%). (ES+) 192 ([MH]+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[C:3]=1[OH:11].CC([O-])(C)C.[Na+].Br[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[CH2:23]([O:22][CH2:21][CH2:20][CH2:19][O:11][C:3]1[C:4]([OH:10])=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH:6]=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(F)c(O)c1O
Reactant: BrCCCOCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccc(F)c(OCCCOCc2ccccc2)c1O

Procedure:
Synthesized according to the methods of general procedure 4 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 4-fluoro-2,3-dihydroxy-benzaldehyde (5.15 g, 32.9 mmol), NaOtBu (6.95 g, 72.3 mmol), DMSO (200 mL), (3-bromo-propoxymethyl)-benzene (8.31 g, 36.3 mmol). Purification: Biotage silica gel chromatography (hexanes/ethyl acetate gradient) generated 4.00 g of a mixture of the title compound and the dialkylated product. This material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.13 (s, 1H), 7.66-7.54 (m, 5H), 7.53-7.33 (m, 1H), 6.92-6.90 (m, 1H), 4.53 (s, 2H), 4.52-4.44 (m, 2H), 3.71-3.62 (m, 2H), 2.18-2.13 (m, 2H). 19F NMR (376 MHz, DMSO-d6 with D2O) δ (ppm): −121.03-−121.08 (m, 1F).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[C:21]([CH:22]=[O:23])=[CH:20][NH:19][N:18]=1.C([O-])(=O)C.[Na+].N>S(=O)(=O)(O)O>[N+:1]([C:16]1[O:12][C:13]([C:17]2[C:21]([CH:22]=[O:23])=[CH:20][NH:19][N:18]=2)=[CH:14][CH:15]=1)([O-:4])=[O:2]
Reactant: O=Cc1c[nH]nc1-c1ccco1
Reactant: O=[N+]([O-])O
Agent: CC(=O)[O-]
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
Add 3 ml of 65% nitric acid dropwise to 11 ml of acetic anhydride at room temperature. Then add 1 drop of concentrated sulfuric acid thereto before stirring for 30 minutes and then incorporating therein 1.5 g of 3-(2-furyl)-1H-pyrazole-4-carboxaldehyde. Stir the resulting admixture for 45 minutes at room temperature before adding 4.8 g of sodium acetate. Heat for 1 hour at 30° C and then for 2 hours at 40° C. Pour the thus-produced solution on ice, neutralize it with concentrated ammonia solution and extract the neutralized solution several times with chloroform. Concentrate by evaporation in vacuum and then chromatograph over a silica gel column with chloroform/ethanol (9:1) to obtain 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde [m.p. 187° to 187.5° C].
Reaction SMILES: [CH:1]1([C:7]([OH:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:10][CH2:11][C:12]#[C:13][CH2:14][N:15](CC2C=CC(OC)=CC=2)[CH2:16][CH3:17])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)[O-]>CO>[CH:27]1([C:7]([OH:33])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][C:12]#[C:13][CH2:14][NH:15][CH2:16][CH3:17])=[O:9])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCN(CC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1)Cc1ccc(OC)cc1
Agent: O=C([O-])Cl
Solvent: CO
Product: CCNCC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
reacting said 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate sequentially with a carbonochloridate and methanol to produce 4-(ethylamino)-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A solution of methyl 2-bromo-5-chlorobenzoate (4.9 g, 19.64 mmol) in THF (50 mL) was cooled to 0° C. and treated with the dropwise addition of LAH (1.0M in THF) (20.62 mL, 20.62 mmol), causing a mild exotherm and gas evolution. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched using the Steinhardt procedure (see Fieser & Fieser, Reagents for Organic Synthesis, p. 584). The resulting precipitate was removed by filtration and washed with ethyl acetate. The combined filtrates were concentrated in-vacuo to yield a colorless oil which solidified upon standing. The residue was purified over a 330 g silica gel column via ISCO, eluting with a 10-100% EtOAc/Hexanes gradient over 30 minutes, to yield the title compound (2.04 g, 47% yield) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.O>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(NCCc2cccc(OC)c2)cc1

Procedure:
A solution of (3-methoxy-phenyl)-acetyl chloride (5.0 g) in ethyl acetate (85 mL) was added to a solution of 4methoxy-phenylamine (3.33 g) in ethyl acetate (50 mL). After 18 h the reaction was poured into water (150 mL). The organic extract was dried over sodium sulfate, filtered through celite and concentrated. The resulting residue was dissolved in tetrahydrofurane (100 mL) then lithium aluminum hydride (5.2 g) was added in small portions over 30 minutes. After 18 h the reaction was slowly poured onto 200 mL of ice. The mixture was filtered through a pad of celite and the collected filtrate was extracted with ethyl acetate (300 mL). The organic extract was dried over sodium sulfate, filtered through celite and concentrated to give the title compound. MS: 258.3 (MH+); HPLC tR: 1.98 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O.N>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:15])=[O:8]
Reactant: CN(C)C=O
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 5-methyl-2-nitrobenzoic acid (17.0 g, 93.8 mmol) and DMF (0.1 mL) in THF (150 mL) was added dropwise oxalyl chloride (13.1 g, 103 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. This solution was added dropwise to aqueous ammonia (8% aqueous solution, 210 mL) under ice-cooling. The reaction solution was concentrated under reduced pressure to evaporated THF, and the precipitated insoluble material was collected by filtration. The filtered cake was washed with water to give 5-methyl-2-nitrobenzamide as a pale-yellow powder (15.3 g, 90%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48]([C:50]1[CH:58]=[CH:57][C:53]([C:54](Cl)=[O:55])=[CH:52][CH:51]=1)#[N:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54](=[O:55])[C:53]2[CH:57]=[CH:58][C:50]([C:48]#[N:49])=[CH:51][CH:52]=2)[CH2:42][CH2:41]1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 49 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 4-cyanobenzoyl chloride as starting materials in 49% yield. LCMS for C32H30ClN8O2 (M+H)+: m/z=593.2.
Reaction SMILES: [C:1]([O:11][CH:12]([C:14]([C:17]([O:19]C)=[O:18])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[NH4+:22]>O>[C:1]([O:11][CH:12]([C:14]([C:17]([O-:19])=[O:18])([F:16])[F:15])[F:13])([C:4]([C:7]([F:8])([F:10])[F:9])([F:6])[F:5])([F:3])[F:2].[NH4+:22]
Reactant: COC(=O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F

Procedure:
The procedure of Preparation 1 was followed except using 16.3 grams of C3F7OCHFCF2COOCH3 instead of the CF3O(CF2)3OCHFCF2COOCH3 and using 7 grams (50 mmol) of a 25% by weight ammonium hydroxide solution in water instead of potassium hydroxide.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[CH2:4].C1C[O:20]CC1.[OH-].[Na+].OO>CCOCC>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH2:4][OH:20])=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: C=CC(C)(C)c1ccc(-c2ccco2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(CCO)c1ccc(-c2ccco2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of 2-[4-(1,1-dimethyl-allyl)-phenyl]-furan (424 mg, 2 mmol) (reference example 51)in THF (4 mL) is added dropwise (1M)borane-THF complex (2.2 mL, 2.2 mmol) and the resulting mixture stirred for 1 hour. To the mixture is added 10% NaOH (1.5 mL) and 30 wt % H2O2 (1.5 mL) and stirred for 1 hour while allowing to warm to 20° C. The mixture is diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 25% ethyl acetate in hexanes) to give 341 mg of the title compound. 1H NMR (CDCl3) δ 1.34 (s, 6H), 1.40 (m, 1H), 1.94 (t, J=8 Hz, 2H), 3.48 (t, J=8 Hz, 2H), 6.45 (m, 1H), 6.60 (m, 1H), 7.35 (d, J=8 Hz, 2H), 7.44 (bs, 1H), 6.61 (d, J=8 Hz, 2H). MS (EI) m/z 230 (M+).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:34]1([NH:44]N)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>>[CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:35]4[C:34](=[C:43]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]5=[CH:37][CH:36]=4)[NH:44][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCc3c(-c4ccccc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-oxo-7-phenylheptyl)-4-piperidinyl]phenyl}propanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 558.2 (M+H)+.