Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=1[O:38][CH3:39]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(CC(C)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CC(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6 g, 18.2 mmol) in acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). The dichloromethane was filtered and concentrated again. The crude material (6.4 g) was purified by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 700 ml; 1% methanol in dichloromethane, 1.4 l). The material thus purified (weight: 2.87 g, 51%) was recrystallized from ethanol (25 ml) to give 2.13 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanone as beige colored crystals, m.p.=118°-119° C.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[OH-].[K+].[CH3:24][N:25]=[C:26]=[O:27]>C1C=CC=CC=1>[CH3:24][NH:25][C:26]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:20])[F:21])=[CH:19][CH:18]=2)[CH2:17]1)=[O:27]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: CN=C=O
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 8 h

Procedure:
The oxalic acid salt of 3-(4-trifluoromethylphenoxy) azetidine (13.0 g., 0.042 mole) was partitioned between 50 ml. of benzene and 50 ml. of potassium hydroxide solution. The benzene layer was dried over calcium sulfate and filtered, and to the stirring dried benzene solution was added 2.6 g. (0.046 mole) of methyl-isocyanate. Stirring was continued overnight. The mixture was concentrated at reduced pressure and the solid residue was recrystallized from a mixture of isopropyl ether-ethyl acetate. The product weighed 7.5 g. (65%) and melted at 154°-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Br:14]Br>>[Br:14][CH:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=2[C:10]1=[O:11]
Reactant: O=C1CCCOc2ccc(Br)cc21
Reactant: BrBr
Product: O=C1c2cc(Br)ccc2OCCC1Br

Procedure:
Following the procedure for 449, Step 1, 7-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one was reacted with bromine to afford the title compound as a white solid. 1H NMR (CDCl3): 7.86 (1H, d, J=2.6 Hz), 7.53 (1H, dd, J=8.7, 2.6 Hz), 6.96 (1H, d, J=8.7 Hz), 4.94 (1H, dd, J=7.6, 6.7 Hz), 4.43 (1H, ddd, J=12.7, 5.6, 4.7 Hz), 4.18 (1H, ddd, J=12.7, 9.7, 4.4 Hz), 2.97-2.87 (1H, m), 2.51 (1H, ddt, J=14.7, 7.6, 4.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[ClH:11].[N:12]([O-])=O.[Na+]>O>[Cl-:11].[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N+:6]#[N:12])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccccc1[N+](=O)[O-]
Product: [Cl-]
Temperature: 65 °C
Yield: 359.8 %

Procedure:
To a 500 mL three-necked flask equipped with a mechanical stirrer are added 60 g of 2-nitroaniline and 134.2 g of concentrated hydrochloric acid. After heating to 65° C., 46 g of water is added after which the reactor is cooled to 0° C. Sodium nitrite (74.2 g, 40% aqueous solution) is slowly added to the slurry while maintaining a temperature of 0° C. The diazonium salt solution is filtered to give 290 g of solution which is stored at −15° C. for later use.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:9]([Si:12](OS(C(F)(F)F)(=O)=O)([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Product: CC(C)[Si](Oc1ccc(Br)cn1)(C(C)C)C(C)C

Procedure:
5-Bromo-2(1H)-pyridinone is allowed to react with triisopropylsilyl-trifluoromethanesulfonate to afford 5-bromo-2-(triisopropylsilyloxy)pyridine having the formula IV. ##STR16##
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(OC2CCCCO2)cc1
Yield: 86 %

Procedure:
4-Hydroxybenzaldehyde (43.4 g, 0.355 mol), dihydropyran (44.4 ml, 0.495 mol), pyridinium p-toluenesulphonate (11.6 g, 0.046 mol, 0.1 mol equiv.) and dichloromethane (300 ml) were stirred for 16 h at room temperature. The mixture was washed with dilute aqueous sodium hydroxide solution (2×300 ml), water (200 ml), brine (300 ml), and finally with water (250 ml), dried over sodium sulphate and evaporated to dryness to leave a dark brown oil(63 g, 87%). This was used without further purification in the following step 1CW02. 1H NMR showed expected signals.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Br-:20].[C:24]1([CH2:23][CH2:22][CH2:21][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 48 h
Yield: 53.8 %

Procedure:
Triphenylphosphine (2.364 g, 9.00 mmol) was added to (3-bromo-propyl)-benzene (1.552 g, 8.00 mmol) in 35 mL toluene in a 100-mL round-bottom flask. The mixture was heated to reflux under argon and stirred 48 h, then concentrated in vacuo. The resulting white amorphous solid was triturated with ether (3×20 mL) to yield 1.984 g (55%) white solid. 1H NMR (CDCl3, 300 MHz) δ7.66-7.83 (m, 15H), 7.19-7.27 (m, 5H), 3.92-4.02 (m, 2H), 3.06 (t, J=7.2 Hz, 2H), 1.92-2.00 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(CC)CC>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (4.18 g, 20.0 mmol), morpholine (2.09 g, 24.0 mmol), Et3N (6.07 g, 60.0 mmol) and EtOAc (30 mL) was stirred at rt for 5 h. The mixture was then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (5.0 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]C(OCC)=O)[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.[CH3:24][Mg]Br.[NH4+].[Cl-].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C1COCC1.CCOCC.CCOC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([CH3:31])([OH:34])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([OH:34])([CH3:31])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Reactant: C[Mg]Br
Agent: O=C(O)/C=C/C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a stirred solution, under N2, of ethyl 3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionate (3.1 g, 9 mmol), in THF (100 ml) was added, dropwise, methylmagnesium bromide (9.0 ml, 27 mmol of a 3M solution in ether). The reaction was stirred at ambient temperature for 16 hours and then a saturated solution NH4Cl was added dropwise, with cooling. The reaction was further diluted with H20, and after extractive workup of the aqueous mixture with EtOAc, 2.8 g of a waxy solid resulted. The solid was dissolved in EtOAc and 3.0 g of fumaric acid was added, and 5.0 g of a fumarate salt was collected, which was contaminated with unreacted fumaric acid. The crude salt was recrystallized from MeOH--Et2O, and then from DMF to afford 1.6 g (45.7%) of the desired compound as a hemifumarate, m.p.=237°-239° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])(=O)C.[K+].[N:15]([O-])=O.[Na+]>CC(O)=O.O>[Cl:9][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[N:15][NH:1][C:2]=12
Reactant: O=N[O-]
Reactant: Cc1ccnc(Cl)c1N
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nccc2cn[nH]c12
Temperature: 25 °C
Reaction time: 66 h
Yield: 45.7 %

Procedure:
To a cooled (internal temperature of <13° C.) mixture of 3-amino-2-chloro-4-methylpyridine (10.14 g, 71.1 mmol, Matrix) and potassium acetate (9.02 g, 92 mmol) in AcOH (200 mL) was added a solution of sodium nitrite (7.36 g, 107 mmol) in water (30 mL) dropwise while maintaining an internal temperature <13° C. The reaction was allowed to warm slowly to rt and stirred for 66 h. The mixture was concentrated under reduced pressure and the residue was basified with saturated NaHCO3. The solid was filtered and washed with water. The solid was stirred over EtOAc overnight and filtered. The filtrate was combined with the organic extracts, evaporated onto silica gel and purified by flash chromatography (Isco (120 gram)) eluting with EtOAc:hexanes (0:1→1:1) to give a white crystalline solid (4.99 g, 46%). MS m/z=153.9, 155.9 [M+H]+. Calculated for C6H4ClN3: 153.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@@H:2]([C:11](O)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(OCC)(=O)C.CO>[CH:20]1[C:19]2[CH:18]([CH2:17][O:16][C:14]([NH:1][C@@H:2]([CH2:11][OH:12])[CH2:3][C:4]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:10])=[O:15])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
A solution of Fmoc-D-Asp(OtBu)-OH (9.0 g, 21.8 mmol) and N,N-diisopropylethylamine (4.6 mL) in TBF (100 mL) at −40° C. was treated with isobutyl chloroformate (3.1 mL, 24.1 mmol), warmed to 0° C. over 30 minutes, cooled to −20° C., and treated slowly with sodium borohydride (1.64 g, 43.6 mmol) and methanol (10 mL). The reaction was gradually warmed to room temperature over 2 hours, diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+))m/e 398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:3]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution (0.1 M) of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate in DMF was treated at 0° C. with NaH (1.3 eq.) and then stirred at 25° C. for 1 h. The solution was treated with tert-butylbromoacetate (1.2 eq.) and stirred 25° C. for 12 h. The mixture was diluted with EtOAc and washed sequentially with HCl (1 N) and brine. The dried organic phase was concentrated and the residue purified by flash chromatography on silica gel (5:95 EtOAc/PE) to afford the title compound (83%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.31-1.53 (m, 3H), 1.42 (s, 9H), 1.64-2.02 (m, 7H), 2.77-2.96 (m, 1H), 3.88 (s, 3H), 5.12 (s, 2H), 7.68 (dd, J 8.4, 1.2, 1H), 7.84 (d, J 8.4, 1H), 8.16 (d, J 1.2, 1H); MS (ES+) m/z 452 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[OH:21])[C:15]([OH:17])=[O:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].O1CCCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15]([OH:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2cc(C(=O)O)ccc2O)C=C(C(C)(C)C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2cc(C(=O)O)ccc2O)cc(C(C)(C)C)c1O
Yield: 63.6 %

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-4-hydroxybenzoic acid, 0.05 g of 5% palladium on charcoal catalyst, 250 ml of ethanol and 50 ml of tetrahydrofuran was placed on a Paar apparatus. Hydrogen uptake was complete in about 10 minutes. The reaction mixture was filtered to remove catalyst. The filtrate was evaporated to give a tan solid which was recrystallized from a mixture of 40 ml of ethanol and 15 ml of water to give 3.2 g of reddish tan granular 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-4-hydroxybenzoic acid, m.p. 254.5°-255° C. (dec). Analysis: Calculated for C21H27NO4 : %C, 70.6; %H, 7.6; %N, 3.9; Found: %C, 71.0; %H, 7.6; %N, 4.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)(O)=[O:2].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O.CN(C)C=O>CCCCCCC>[Cl:23][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C(Cl)c1ccc2c(c1)COC2=O
Temperature: 25 °C

Procedure:
5-Carboxyphthalid (53 g, 0.3 mole) was suspended toluene (200 mL) and thionylchloride (44 g, 0.6 mole). N,N-dimethylformamide (DMF) (1 mL) was added and the mixture was heated at reflux temperature for 3 hours. The mixture was cooled to room temperature and n-heptane was added (200 ml). The crystals formed were collected and washed with heptane (100 mL). Yield 52 g, 88%. DSC onset: 131° C. 1H NMR (CDCl3, 500 MHz): 5.47 (2H, s), 8.06 (1H, d , J=7.5 Hz), 8.28(1H, d, J=7.5 Hz), 8.3(1H, s). 13C NMR (CDCl3, 125 MHz): 69.4, 125.1, 126.1, 131.1, 131.6, 137.8, 146.6, 167.4, 169.0.
Reaction SMILES: [N:1]1([C:10](=[O:12])[CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:13]Br>C(O)(=O)C>[Br:13][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([C:10](=[O:12])[CH3:11])[CH2:2][CH2:3]2
Reactant: BrBr
Reactant: CC(=O)N1CCc2ccccc21
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.7 %

Procedure:
To a solution of 1-(2,3-dihydro-indol-1-yl)-ethanone (58.0 g, 0.36 mol) in acetic acid (3000 mL) was added Br2 (87.0 g, 0.54 mol) at 10° C. The mixture was stirred at room temperature for 4 h. The precipitate was collected via filtration to give crude 1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanone (100 g, 96%), which was used directly in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccccc1CBr
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-(bromomethyl)-2-(trifluoromethyl)benzene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (87%) as a colorless solid: mp 137-138° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.6 Hz, 1H), 7.52-7.33 (m, 2H), 7.22-7.13 (m, 3H), 7.07-7.00 (m, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.08 (d, J=17.1 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.23-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 127.9 (q, 2JC-F=30.8 Hz), 127.6, 126.8, 126.4 (q, 5JC-F=5.8 Hz), 124.4 (q, 1JC-F=273.8 Hz), 124.1, 123.8, 120.8, 111.6, 109.2, 99.6, 80.3, 64.5, 64.0, 58.2, 40.6 (q, J=3.4 Hz); MS (ES+) m/z 454.0 (M+1). Anal. Calcd. for C26H18F3NO4: C, 66.22; H, 4.00; N, 3.09. Found: C, 66.16; H, 4.11; N, 3.07.
Reaction SMILES: C1(O)C=CC=CC=1.B(F)(F)F.CCOCC.[CH2:17]1[CH:21]2[CH:22]3[CH:26]=[CH:25][CH:24]([CH:20]2[CH:19]=[CH:18]1)[CH2:23]3.C1CC=CC=1.C=CC(=C)C>>[CH2:17]1[CH:21]2[C@@H:22]3[CH:26]=[CH:25][C@H:24]([CH:20]2[CH:19]=[CH:18]1)[CH2:23]3
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: C1=CCC=C1
Agent: FB(F)F
Solvent: C=CC(=C)C
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a reactor equipped with a stirrer, condenser, thermowell and heater add 1882 gms (20 moles) of phenol and 8 gms (0.4% based on total weight) of boron trifluoride etherate. Heat to 70° C. and add 132 gms (~1 mole) of a C10 diene stream containing mainly dicyclopentadiene and cyclopentadiene-isoprene codimers over a 20 minute (1200 s) period. Increase the temperature to 150° C. over a 3 hour (10,800 s) time period and hold for about 3 hours (10,800 s). Distill off unreacted phenol with a finishing temperature of 210° C. and less than 5 mm Hg. The recovered product is a dicyclopentadiene bisphenol with an average functionality of 2.07.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11]O.O=S(Cl)[Cl:15].C(Cl)Cl>>[Cl:15][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(CO)nc2ccccc21
Solvent: ClCCl
Product: Cn1c(CCl)nc2ccccc21

Procedure:
A solution of (1-methyl-1H-benzoimidazol-2-yl)-methanol (500 mg, 3.08 mmol) and SOCl2 (1.1 mL) in DCM (2 mmol) was stirred at room temperature for 3 hours. After evaporation of the solvents, 2-chloromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) was obtained and was used without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12]>COCCOC.O>[Br:12][CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OCc1cc(F)ccc1Cl
Reactant: BrP(Br)Br
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-chloro-5-fluorophenyl)methanol (24, 25.5 g, 159 mmol) in dry DME (200 mL) at 0° C. was added a solution of PBr3 (25.8 g, 95.2 mmol) in dry DME (150 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at RT for another 3 h. The mixture was diluted with water (300 mL), and extracted with 1:1 petroleum-ether-EtOAc (200 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give 2-(bromomethyl)-1-chloro-4-fluorobenzene (25).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:5]([CH:3]=[O:2])[N:6]=1
Reactant: COC(=O)c1cc2ccccc2cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2cn1
Yield: 85.7 %

Procedure:
3-Isoquinolinecarboxaldehyde (7 g, 84%) was prepared by reduction of 3-isoquinolinecarboxylic acid methyl ester (10 g, 52 mmol) with 1M LAH (27 ml in THF,27 mmol) in 300 ml of dry THF at -78° C. for 30 minutes. The mixture was quenched with 7 ml of acetic acid, concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 2:1) to afford 7 g (84%) of 3-iso-quinolinecarboxaldehyde.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].O>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7](=[O:9])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccncc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccncc1
Reaction time: 0.67 h

Procedure:
A suspension of 4-picolinic acid (3.00 g, 24.4 mmol) and 1,1-carbonyldiimidazole (4.74 g, 29.2 mmol) in CH2Cl2 (35 mL) was stirred for ˜40 minutes, at which time it became a clear solution. After the addition of N,O-dimethylhydroxylamine hydrochloride (2.85 g, 29.2 mmol), the mixture was stirred at room temperature for 22 hours. Water was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water once, and the aqueous layer was back extracted with CH2Cl2. The organic phases were combined, dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (80 g silica gel column, 100% EtOAc) to provide the title compound as a clear oil.