Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5](=[O:40])[C:6]([CH3:39])([CH3:38])[CH2:7][C:8]1[N:9]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([C:16]=1[S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH:12][CH:11]=2)C=C.CO.[Li+].[OH-].Cl>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:9]2[C:10]3[C:15](=[CH:14][C:13]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:12][CH:11]=3)[C:16]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:7][C:6]([CH3:39])([CH3:38])[C:5]([OH:40])=[O:4])=[CH:32][CH:33]=1
Reactant: C=CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccccn3)cc12
Temperature: 25 °C

Procedure:
The compound from Step 1 (133 mg) was dissolved in THF (5 mL), MeOH (3 mL), and 1N LiOH (1.2 mL) and heated at 55° C. for 1 hour. After cooling to room temperature, the mixture was acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was swished in ether/hexane, affording the title compound as a white solid, m.p. 186.2°-187.7° C.
Reaction SMILES: [OH:1]O.[CH3:3][O:4][CH:5]1[CH2:9][CH:8]=C[CH2:6]1.[CH:10]([OH:12])=O>>[OH:1][C@@H:8]1[CH2:9][CH:5]([O:4][CH3:3])[CH2:6][C@H:10]1[OH:12]
Reactant: OO
Reactant: COC1CC=CC1
Reactant: O=CO
Product: COC1C[C@@H](O)[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
88% Formic acid (90 ml) and 30% hydrogen peroxide (3.17 ml) were added to 4-methoxy-1-cyclopentene thus obtained, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 35% aqueous solution of sodium hydroxide was added to the residue to alkalify the reaction mixture, followed by stirring at 50° C. for 10 minutes. The reaction mixture was cooled to room temperature and extracted with ethyl acetate to dry the organic layer over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=5:95) to obtain the title compound (1.21 g) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][C:11]1([CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]1[OH:20])C#N>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[O:20][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)cc1
Reactant: N#CC1(O)C=CC=C(F)C1O
Product: N#Cc1ccc(Oc2cccc(F)c2Oc2ccc(C#N)cc2)cc1
Yield: 89.4 %

Procedure:
The compound 1,2-bis-(4-cyanophenoxy)-3-fluorobenzene was prepared according to the procedure described in Example 1 by reacting 4-fluorobenzonitrile with 1,2-dihydroxy-3-fluorobenzonitrile. The product was recrystallized from ethanol/water (4:1). The yield was 89.4% of the title compound with the formula: ##STR9##
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH3:9])=[N:6][CH:7]=1.Cl.[NH2:23][C@H:24](C1C=CC(C#N)=NC=1)C>>[C:7]([C:2]1[N:23]=[CH:24][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1)#[N:6]
Reactant: C[C@H](N)c1ccc(C#N)nc1
Reactant: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1
Agent: Cl
Product: C[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(C#N)nc1

Procedure:
Prepared analogously to Compound 2 using IM46 and commercially available 5-((S)-1-amino-ethyl)-pyridine-2-carbonitrile hydrochloride (Supplier Netchem Inc., Catalog No 549493). Yield=0.104 g (20%). %). 1H NMR (600 MHz, DMSO) δ 8.76 (d, 1H), 8.71 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.29 (m, 2H), 7.19 (m, 1H), 7.12 (d, 2H), 5.03 (m, 1H), 2.21 (m, 1H), 1.92 (m, 1H), 1.40 (d, 3H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z) 292.0 (MH+), tR=1.31 min (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([F:18])[C:15]=2[CH:16]=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].C(Cl)Cl>C1COCC1.O>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([F:18])[C:15]=2[CH2:16][OH:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(-c2cncc(F)c2C=O)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2cncc(F)c2CO)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To the solution of 2-chloro-4-(5-fluoro-4-formylpyridin-3-yl)benzonitrile (45 mg, 0.17 mmol) in THF (3 mL) and water (1 mL) was added sodium borohydride (6.5 mg, 0.17 mmol) at 0° C. This reaction mixture was stirred for 0.5 h at room temperature. After addition of CH2Cl2, the organic layer was washed with saturated NaCl solution and extracted with DCM for five times. The combined extracts were dried over Na2SO4, filtered, and evaporated. The resulting mixture was passed through a pad of silica gel, rinsed with 0-50% EtOAc/heptane, and evaporated to give 2-Chloro-4-(5-fluoro-4-hydroxymethyl-pyridin-3-yl)-benzonitrile (21 mg, 46%) as a white solid. ESI-MS m/z: 263 [M+1]+, Retention time 1.11 min. 1H-NMR (CDCl3, 400 MHz) δ 4.56 (s, 2H), 7.66 (dd, J=8.4, 1.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:22]>O1CCCC1.O.C(#N)C>[Li+:22].[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH:4]([CH3:19])[C:3]([O-:20])=[O:2])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)CN1CCN(c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CC(CN1CCN(c2ccc(Cl)cc2)CC1)C(=O)[O-]
Yield: 41.9 %

Procedure:
3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-methyl-propionic acid methyl ester (586 mg; 1.98 mmol, prepared in accordance with Example 59) and lithium hydroxide (60 mg; 2.50 mmol) are suspended in a mixture of tetrahydrofuran (4 mL) and water (1 mL). The resulting mixture is irradiated in a mono-mode microwave oven for 50 minutes at 100° C. The mixture is then diluted with acetonitrile until precipitation occurs. The solid formed is then filtered and dried under high vacuum to afford the desired product (238 mg; 0.83 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9]COCCOC)[C:3]=1[CH2:16][CH2:17][CH:18]1[O:23][C:22](=[O:24])[CH2:21][CH:20]([OH:25])[CH2:19]1>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH2:16][CH2:17][CH:18]1[O:23][C:22](=[O:24])[CH2:21][CH:20]([OH:25])[CH2:19]1
Reactant: COCCOCOc1cc(Cl)cc(Cl)c1CCC1CC(O)CC(=O)O1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: O=C1CC(O)CC(CCc2c(O)cc(Cl)cc2Cl)O1
Temperature: 20 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Zinc bromide (2.4 g, 10 mmole) was added to a solution of 6-{2-[2,4-dichloro-6-(2-methoxyethoxymethoxy) phenyl]ethyl}-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (780 mg, 2 mmole) in methylene chloride (12 ml). The resulting mixture was stirred at 20° C. for 2 hours, then quenched with saturated sodium bicarbonate solution (50 ml) and diluted with ether (200 ml). The ethereal layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on a 50 mm low-pressure column with 6 inches of silica gel (230-400 mesh). The column was eluted with 470 ml of methylene chloride-acetone (4:1, v:v). The next 330 ml provided the title compound as a golden glass (100 mg., 16%): pmr (CDCl3) δ2.62 (2H, d), 4.29 (H, m), 4.78 (H, m), 6.87 (2H, s).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)#[N:6]>O.C(O)(=O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:7](=[N:1][OH:3])[C:5]#[N:6]
Reactant: O=N[O-]
Reactant: N#CCc1nc2ccccc2s1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(=NO)c1nc2ccccc2s1

Procedure:
A solution of 7.8 g (0.1 mol) of NaNO2 in 20 ml of water is added dropwise at room temperature to 17.4 g (0.1 mol) of 2-cyanomethyl-benzthiazole in 50 ml of glacial acetic acid. The end product is filtered off after 2 hours and washed with water: 19.5 g (96% of theory), melting point >170° (decomposition).
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)CC(OC(C)=O)C(Cl)(Cl)Cl
Yield: 91 %

Procedure:
A solution of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene (65 g) in pyridine (100 ml) was heated with acetic anhydride (65 ml) at 100° C. for 3 hours. The reaction mixture was poured into water (600 ml) and the resulting solution extracted with ether (3×200 ml). The combined other phases were dried over MgSO4 and the ether was evaporated. Distillation and re-distillation yielded 71.4 g (91%) of 1,1,1-trichloro-2-acetoxy-4-methyl-4-pentene. B.p. 92°-96° C./11 mm Hg.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8]C=2)[CH:4]=[CH:3][CH:2]=1.[C:11](=[O:13])=O.[OH2:14]>>[CH:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH:7]=[CH:8][C:11]2=[O:13])=[O:14])=[CH:10][CH:1]=1
Reactant: O=C=O
Reactant: O
Reactant: c1ccc2ccccc2c1
Product: O=C1C=CC(=O)c2ccccc21

Procedure:
A smaller portion of naphthalene is at the same time converted to 1,4maleic anhydride, or it is completely oxidized (to carbon dioxide and water). If the heat of reaction is too low, a greater amount of 1,4naphtaquinone is produced. If the temperature is too high, the proportion of maleic anhydride increases and the major part of naphthalene is completely oxidized. A part of orthoxylene is also converted to maleic anhydride or it undergoes complete oxidation. As a by-product of partial orthoxylene oxidation, phthalate is produced.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([C:12](C)([CH3:15])[CH:13]=C)[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21](=[O:23])=[O:22].CC(C)=O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[Si:1]([N:8]1[CH:11]([C:12]([C:21]([OH:23])=[O:22])([CH3:13])[CH3:15])[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: C=CC(C)(C)C1C(C(C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(O)C1C(=O)N([Si](C)(C)C(C)(C)C)C1C(C)(C)C(=O)O

Procedure:
A solution of 1-(t-butyldimethylsilyl)-3-(1-hydroxyethyl)-4-(1,1-dimethyl-prop-2-enyl)-azetidin-2-one (3.0 mmol) in dry methylene chloride (30 ml) is cooled to -78° C. (dry ice-acetone) and a stream of ozone is bubbled through until the reaction mixture becomes blue. The ozone flow is then stopped and the reaction is purged by bubbling through nitrogen until the blue color disappears. Solid m-chloroperbenzoic acid (3.0 mmol) is added and the cold bath is removed. When the reaction mixture reaches room temperature, the flask is fitted with a reflux condenser and the mixture is heated at reflux for three days. Removal of solvents in vacuo gives a crude product which is chromatographed on silica gel (2% glacial acetic acid in methylene chloride) to yield 6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:12]Br.[CH2:14]([O:21][C:22](=[O:26])[NH:23][CH2:24][CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C=O)C>[CH2:14]([O:21][C:22](=[O:26])[N:23]([CH2:12][C:3]1[CH:4]=[C:5]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[CH2:24][CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCNC(=O)OCc1ccccc1
Reactant: CC(C)(O)c1ccc(Br)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(C(C)(C)O)ccc1Br)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To 2-(4-bromo-3-bromomethyl-phenyl)-propan-2-ol (0.255 g, 0.83 mmol) and ethyl-carbamic acid benzyl ester (0.446 g, 2.49 mmol) in DMF (15 mL) was added sodium hydride (60% in mineral oil; 0.103 g, 2.57 mmol), and the reaction was stirred for 30 minutes. The mixture was quenched with H2O and worked-up. The residue was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCc2c(F)cccc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(OCc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(4-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 4.76 g, 12.6 mmol) in dichloromethane (40 ml) was treated with trifluoroacetic acid (20 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to provide the title compound as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:39]4[CH2:40][CH2:41][CH:36]([O:35][CH3:34])[CH2:37][CH2:38]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: COC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCC(OC)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-methoxy-piperidine. ES-MS m/e (%): 484 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Yield: 92 %

Procedure:
A 200 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with a solution of 22.0 g of piperazine in 20 ml of o-xylene, a solution of 6.70 g of bromobenzene in 20 ml of o-xylene, and a solution of 5.66 g of NaOBut in 20 ml of o-xylene, and further with a solution of 4.5 mg of palladium acetate in 5 ml of o-xylene (the ratio of palladium atom/bromobenzene=0.05% by mole). The flask was flushed with nitrogen for about 20 minutes while the content was stirred, and 0.2 ml of tri-tert.-butylphosphine was added. Then the mixture was heated to 120° C., and maintained at that temperature for 3 hours with stirring. After completion of the reaction, 80 ml of water was added to cool the reaction product. The mixture was introduced in a separatory funnel and the organic phase was separated. The lower aqueous phase was extracted with 40 ml of o-xylene. The organic phase was dried over sodium sulfate. Gas chromatographic analysis of the obtained product by the internal standard method revealed that the intended arylamine, i.e., N-phenylpiperazine was obtained in a yield of 92% by mole.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)C(O)=O)(=[O:3])[CH3:2].C1N=CN([C:19]([N:21]2C=N[CH:23]=[CH:22]2)=[O:20])C=1.[N+:26]([C:29]1[CH:35]=CC(N)=[CH:31][CH:30]=1)([O-:28])=[O:27].O>CN1CCCC1=O>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:7][C:6]=1[C:19]([NH:21][C:22]1[CH:23]=[CH:35][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 57.5 °C
Reaction time: 18 h
Yield: 54.7 %

Procedure:
A mixture of 3-acetamidobenzoic acid (C1) (5.30 g, 29.58 mmol) and CDI (5.75 g, 35.50 mmol, 1.2 equivalent) in N-methylpyrrolidinone (20 mL) was heated at 55-60° C. for 2 h. 4-Nitroaniline (6.13 g, 44.37 mmol, 1.5 equivalent) was then added and the mixture was heated to 140° C. for 4 h, then poured into water (400 mL) and stirred for 18 h. The resulting precipitate was filtered and washed sequentially with water and CH2Cl2 and then crystallized from MeOH to give C2 (4.84 g; 55%) as a yellow solid; mp (MeOH) 259-261° C.; 1H NMR [(CD3)2SO] δ 10.80 (s, 1 H, NH), 10.15 (s, 1 H, NH), 8.29 (m, 2 H, H-{acute over (3)}& H-{acute over (5)}), 8.12 (t, J=1.8 Hz, 1 H, H-2), 7.84 (br dd, J=8.1, 1.2 Hz, 1 H, H-6), 7.65 (td, J=7.8, 2.5 Hz, 1 H, H-4), 7.48 (t, J=7.9 Hz, 1 H, H-5), 2.08 (s, 3H, COCH3); Anal. Calc. For C15H13N3O4: C, 60.2; H, 4.4; N, 14.0; found C, 60.4; H, 4.6; N, 14.1%.
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[F:28][C:29]([F:38])([F:39])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2cccc(C(F)(F)F)c2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 3-(trifluoromethyl)benzyl chloride to form 1-(3-trifluoromethylbenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 133°-135° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.O1CCOCC1>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][N:14]([C@@H:10]3[CH2:9][NH:8][CH2:12][C@H:11]3[OH:13])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCCN(c3ccc(Cl)cc3)CC2)C1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O[C@@H]1CNC[C@H]1N1CCCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.2 %

Procedure:
To a solution of trans-3-[4-(4-Chloro-phenyl)-[1,4]diazepan-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.820 g, 2.08 mmol) in methylene chloride (1 mL) was added 4 N HO/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour, upon which a brown precipitate formed. The reaction was concentrated in vacuo to yield 0.930 g (−100%) of the title compound. ESI-MS m/z: 296 (M+1), FAS method rt: 0.83 min.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.C1(C#C)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>>[CH2:1]1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Solvent: C#Cc1ccccc1
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reaction time: 0.07 h

Procedure:
A 10.0 gram (75.6 mmol) amount of dicyclopentadiene was added to a 20 ml scintillation vial. A 5.0 milligram (7.2 μmol) amount of RuClH(H2)(PCy3)2 was added. Ten equivalents of phenylacetylene and hexachloroethane per equivalent of RuClH(H2)(PCy3)2 were added via the addition of 1.0 mls each of a 72 mM solution of phenylacetylene and hexachloroethane, respectively. The ring opening polymerization of dicyclopentadiene was observed by a rapid thickening of the solution to a rubbery viscous material. After 4 minutes, the material was a rubbery solid. After 24 hours, a hard rubbery solid was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[N:31][N:30]=[CH:29]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](O)([C:35]([F:38])(F)F)=O.[Al].CN(CCO)C.Cl.[N+](C1C=CC(OC(=O)[NH:59][C:60]2[CH:61]=[N:62][C:63]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)=[CH:64][CH:65]=2)=CC=1)([O-])=O>C(Cl)(Cl)Cl>[N:66]1([C:63]2[N:62]=[CH:61][C:60]([NH:59][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]6[CH:32]=[N:31][N:30]=[CH:29]6)=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:65][CH:64]=2)[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1.[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:35]([F:38])=[CH:33][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCn4cnnc4)ccc23)CC1
Reactant: O=C(Nc1ccc(N2CCOCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)CCO
Agent: Cl
Agent: [Al]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Product: O=C(Nc1ccc(N2CCOCC2)nc1)N1CCC(c2ncnc3cc(OCCCn4cnnc4)ccc23)CC1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
The crude 4-[7-(3-[1,2,4]Triazol-4-yl-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester, as prepared in the previous step, was treated with TFA (70 μL) at 100° C. in a sealed vial for 10 min (aluminum block). CHCl3 (450 μL) and DMEA (140 μL, 1.3 mmol) were added, and one-half of the resulting homogeneous amber solution was treated with (6-morpholin-4-yl-pyridin-3-yl)-carbamic acid-4-nitrophenyl ester hydrochloride (22 mg, 58 μmol), as prepared in Example 80a, and stirred at 40° C. for 1.5 hr. (The other one-half of the homogenous solution was diverted to the synthesis given in Example 114.) The reaction was then partitioned with 2M K2CO3 (2 mL) and DCM (2 mL), and the aqueous layer was extracted with 9:1 DCM/MeOH (1×2 mL). The combined organic layers were concentrated and the residue was partially purified with a 5 g silica flash cartridge (97:3 acetone/MeOH eluent with 2% DMEA), and further purified with HPLC (C18 column) to provide the title compound as a powder after lyophilization [2.1 mg, 8.1% overall from 4-(7-fluoro-quinazolin-4-yl)-piperidin-1-carboxylic acid tert-butyl ester.] 1H-NMR (400 MHz, 95:5 CDCl3/CD3OD) δ 9.12 (s, 1H), 8.43 (dd, 1H), 8.30 (br s, 2H), 8.13 (m, 2H), 7.32 (m, 1H), 7.26 (dd, 1H), 6.96 (d, 1H), 4.37 (m, 4H), 4.21 (t, 2H), 3.88 (m, 4H), 3.75 (m, 1H), 3.59 (m, 4H), 3.14 (m, 2H), 2.42 (pentet, 2H), 2.16-1.95 (m, 4H). LC/MS (ESI) calcd mass 543.3, found 544.1 (MH)+.