Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.Cl.[CH3:22][NH:23][O:24][CH3:25].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:25][O:24][N:23]([CH3:22])[C:18]([C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1)=[O:20]
Reactant: CNOC
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of acid 24 (0.35 g, 1.3 mmol), DMAP (0.5 g, 4.1 mmol), N,O Dimethylhydroxyl amine HCl (0.5 g, 5.1 mmol) in DMF (15 ml) was added EDCI (0.5 g, 2.6 mmol) and the reaction was stirred at rt for 1 hr. The reaction was then poured into 2N HCl and extracted with EtOAc, The EtOAc was dried, concentrated, and the resulting solid was triturated with CH2Cl2 and collected by filtration to give 119 as a white solid (0.22 g, 55%): Mp=125–127° C.; 1NMR (DMSO-d6) δ 9.88 (br s, 1 H), 9.44 (s, 1 H), 7.65(d, 2 H, 8.6 Hz), 7.08 (br s, 1 H), 6.97 (d, 1 H, J=2.3 Hz), 688 (d 2 H, J=8.6 Hz), 6.71 (d, 1 H, J=2.6 Hz), 3.59 (s, 3 H), 3.30 (s. 3 H): MS 312[M−H]−
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11]OS(C)(=O)=O)[CH:5]=[CH:4][N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C>COCCOC>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:11][C:10]2[CH:17]=[CH:18][CH:19]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:29][C@@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CS(=O)(=O)OCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 64 %

Procedure:
Intermediate 125 Methanesulfonic acid 3-(2-chloro-pyrimidin-4-yl)-benzyl ester (0.70 g) and Intermediate 126 2-(S)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.61 g) with diisopropylethylamine (0.70 mL) in ethylene glycol dimethyl ether (20 mL) was refluxed for 3 hours, cooled to room temperature, evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water (3×), brine, dried over dried over Na2SO4, chromatographed on silica gel (dichloromethane:methanol=98:2) to give 0.60 g of oily product with yield 64%. LC-MS showed the product had the expected M+H+ of 403. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.0 (s, 1H) 7.9 (d, 1H) 7.6 (d, 1H) 7.5 (m, 2H) 4.2 (S, 1 h) 3.8 (d, 1H) 3.4 (m, 2H) 3.0 (m, 1H) 2.7 (d, 1H), 2.6 (d, 1H) 2.1 (m, 2H) 1.5 (s, 9H) 1.2 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9]([NH:11][C:12]1[N:13]=[C:14](Br)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)#[CH:26].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9](=[O:10])[NH:11][C:12]1[N:13]=[C:14]([C:26]#[C:25][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(Br)n1
Reactant: C#Cc1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#Cc2ccsc2)n1

Procedure:
A mixture of tert-butyl-N-[1-[(1-bromoisoquinolin-3-yl)amino]-1-oxopropan-2-yl]-carbamate B4a (150 mg, 0.38 mmol), 3-ethynylthiophene (45 mg, 0.42 mmol), copper(I) iodide (7 mg, 0.04 mmol), Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) and DIPEA (200 μl, 2 mmol) is stirred under argon atmosphere in NMP (1 ml) for 1 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 102 mg (64%). HPLC-MS: M+H=422; tR=1.99 min (*Method—4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH:23]([CH3:25])[CH3:24].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH:23]([N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:14]1=[O:21])([CH3:25])[CH3:24]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: CC(C)Br
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C(C)C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-bromopropane as described for compound 8. Purified by chromatography (dichloromethane). Crystallized from diethyl ether/petroleum ether (60-95° C.). M.p. 79-81° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[Br:13]Br>C(Cl)Cl>[Br:13][CH2:11][C:10]([C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1cc(F)c(F)cc1F
Solvent: ClCCl
Product: O=C(CBr)c1cc(F)c(F)cc1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A 1 L 3-neck round bottom flask was charged with 1-(2,4,5-trifluorophenyl)ethanone (49.7 g, 285 mmol) and DCM (350 mL). The flask was equipped with a 250 mL dropping funnel that contained a solution of bromine (14.6 mL, 283 mmol) in DCM (125 mL). This solution was added to the reaction flask over about 1 h at about 23° C. Once addition of the solution was complete, the reaction mixture was stirred for about 1 h at about 23° C. Ice water was added to the reaction flask and the layers were stirred for about 15 min. The layers were separated and the organic solution was then washed with water and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid (70.3 g, 97%): LC/MS (Table 1, Method b) Rt=2.20 min; MS m/z 251.0/253.0 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:22]([CH3:28])([CH3:27])[CH:23]([OH:26])CO)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.C(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>O>[C:1]1([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:22]([CH3:27])([CH3:28])[CH:23]=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(c1[nH]c2ccccc2c1CCNC(=O)OCc1ccccc1)C(O)CO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C=O)c1[nH]c2ccccc2c1CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (±)-N-[2-[2-(2,3-dihydroxy-1,1-dimethylpropyl)-1H-indol-3-yl]ethyl]-carbamic acid phenylmethyl ester (0.323 g, 0.81 mol) in 1:1 acetone/CH2Cl2 (19.5 mL) was added NaIO4 (0.350 g, 1.64 mmol) in H2O (2.2 mL). The reaction mixture was stirred for 3 h at rt. Solid Na2SO4 was added. The mixture was filtered. The filtrate was extracted with CH2Cl2. The CH2Cl2 extracts were dried, filtered, and concentrated to an oil. This oil was purified by silica chromatography to give the title compound: TLC Rf=0.31 (1:1 heptane/EtOAc); MS (ESI+) m/z 365.2; 1H NMR (300 MHz, CDCl3) δ 9.56 (1H), 8.11 (1H), 7.64 (1H), 7.37 (5H), 7.21 (1H), 7.13 (1H), 5.14 (2H), 4.92 (1H), 3.45 (2H), 2.95 (2H), 1.60 (6H).
Reaction SMILES: C1([I:7](OC(=O)C(F)(F)F)OC(=O)C(F)(F)F)C=CC=CC=1.[CH3:22][N:23]1[C:27]2[N:28]=[N:29][CH:30]=[C:31]([OH:32])[C:26]=2[C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:24]1.II.N1C=CC=CC=1>C(Cl)Cl>[I:7][C:30]1[N:29]=[N:28][C:27]2[N:23]([CH3:22])[N:24]=[C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:26]=2[C:31]=1[OH:32]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: Cn1nc(-c2ccccc2)c2c(O)cnnc21
Agent: II
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nc(-c2ccccc2)c2c(O)c(I)nnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.7 %

Procedure:
Phenyl[bis(2,2,2-trifluoroacetoxy)]-λ3-iodane (190 mg, 0.43 mmol) was added to a suspension of 1-methyl-3-phenyl-pyrazolo[3,4-c]pyridazin-4-ol (166 mg, 0.73 mmol) in CH2Cl2 (3.7 mL), followed by the addition of iodine (111 mg, 0.43 mmol) and pyridine (71 μL). The reaction mixture was stirred at room temperature for 16 h, then filtered. The collected solid was washed with CH2Cl2 and dried, to yield the title compound (160 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:31][C:32](Cl)=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1C=CC=CC=1>[C:32](=[O:33])([O:31][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 1.24 g. of chloroformic acid n-nonyl ester as in Example 1. The 2.026 g. of yellowish, turbid oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.646 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-nonyl carbonate obtained melts at 53.0°-53.1° and has a clearing point of 70.0°. The compound is smectic up to 68.1°. UV (EtOH): ε271 = 26,600.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH2:11]([OH:13])[CH3:12].C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([O:13][CH2:11][CH3:12])[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1nc(Cl)nc(OC)n1
Reaction time: 1 h

Procedure:
The 2,4-dichloro-6-methoxy-s-triazine obtained as described in Example A-3 is suspended in acetone, 46 parts of ethanol and 90 parts of sodium bicarbonate are slowly added, and the reaction is carried out at a temperature of between 40° and 50° C. for about one hour. The mixture is then evaporated to give the compound 2-chloro-4-methoxy-6-ethoxy-s-triazine as a powder which contains electrolyte salts and serves as the monochloro-triazine starting compound in the synthesis of dyestuffs according to the invention.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8]OS(=O)O[CH2:4]1)[CH3:2].[C-:12]#[N:13].[Na+].[OH2:15]>CS(C)=O>[CH2:1]([C:3]([CH2:8][OH:15])([CH2:10][CH3:11])[CH2:4][C:12]#[N:13])[CH3:2]
Reactant: O
Reactant: CCC1(CC)COS(=O)OC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC)(CO)CC#N
Temperature: 120 °C
Yield: 31 %

Procedure:
Step B To the solution of 5,5-diethyl-[1,3,2]dioxathiane 2-oxide (7 g, 39 mmol) in anhydrous dimethyl sulfoxide (40 mL) was added NaCN (3.9 g, 80 mmol). The reaction mixture was heated at 120° C. for 20 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:2) to give 3-ethyl-3-hydroxymethyl-pentanenitrile as a yellow oil (1.7 g, 31%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:18])[C:12]=3[C:11]3=[N:19][O:20][C:21]([CH3:22])=[C:10]3[C:9]2=[O:23])[CH2:3]1.[C:24]1([NH:30][CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=N)C.CC1C=C(C)C=C(C)N=1>CN(C)C=O>[Cl:18][C:13]1[C:12]2[C:11]3[C:10](=[C:21]([CH3:22])[O:20][N:19]=3)[C:9](=[O:23])[N:8]([CH:4]3[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:32](=[O:33])[CH2:31][NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:3]3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Reactant: O=C(O)CNc1ccccc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)CNc3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous dimethylformamide (10 mL) in a nitrogen atmosphere was used to dissolve 5-(3-aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one (50 mg; 0.151 mmol), N-phenylglycine (29.6 mg; 0.196 mmol; 1.3 equiv), 1-hydroxy-7-azabenzotriazole (26.7 mg; 0.196 mmol; 1.3 equiv), 1-[3-(dimethylamino)propyl[-3-ethylcarbodiimide hydrochloride (37.6 mg; 0.196 mmol; 1.3 equiv), and 2,4,6-trimethylpyridine (199 μL; 1.51 mmol; 10 equiv). After overnight stirring at room temperature, the reaction solution was treated in a manner similar to Example 159. The resulting material was purified by three consecutive radial chromatography runs on a 2 mm thick silica gel rotor with a 1% methanol/dichloromethane (v/v) mobile phase, a 1% methanol/0.25% triethylamine/dichloromethane (v/v/v) mobile phase, and a 5% acetonitrile/dichloromethane mobile phase. The desired product was isolated as a white solid 56% yield (30 mg). MS(ES) calc'd: [M+M]+=465.16 m/z; [M−H]−=463.16 m/z; [M+OAc]−=523.16 m/z. Found: 465.1 m/z; 463.2 m/z; 523.2 m/z.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[I:17]I.S(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1c(F)cc(I)cc1C(=O)O
Yield: 63 %

Procedure:
To a solution of 999 mg (6.44 mmol) of 2-amino-3-fluorobenzoic acid in 35 mL of water was added 500 mg (5.95 mmol) of sodium bicarbonate. The reaction was stirred and 1.77 g (6.99 mmol) of iodine was slowly added. The reaction was stirred at room temperature for 48 hours. To the solution was added an aqueous solution of sodium bisulfite and the solution was stirred vigorously for 30 minutes. The precipitate was collected by vacuum filtration and washed with water. The brown solid was dried overnight to afford 1.14 g (4.06 mmol, 63% yield) of 2-amino-3-fluoro-5-iodo-benzoic acid. 1H NMR (500 MHz, DMSO-d6) δ 7.79 (t, 1H), 7.58 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>C1COCC1.[Br-].[Na+]>[CH3:4][C:2]([NH:5][C:6]([C:8]1[C:13]([CH2:14][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:1])[CH3:3]
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: Fc1ccc(CCl)cc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a cooled (-40° C.) solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide (38.4 g, 0.2 mole) in dry THF (250 mL) is added n-butyl lithium (185 mL, 0.44 mole). Then sodium bromide (1.9 g, 18 mmol.) is added and is allowed to stir for 15 minutes. 4-Fluorobenzylchloride (31.8 g. 0.22 mole) was added and the reaction is allowed to stir for 21/2 hours while warming up to -5° C. The reaction is then quenched with water and the product is extracted twice with ethyl acetate followed by washing twice with brine. The organic phase is dried over Na2SO4, filtered and solvent is removed to give desired compound (60.0 g) in 99% yield, m.p. 59°-61° C.
Reaction SMILES: [C:1](=[O:13])([O:3][C:4]1([C:9](C)(C)C)[CH:6](CBr)[CH2:5]1)[NH2:2].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18]O1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:32][CH2:31]2)[C:23]1=[O:42]>>[C:4]([O:3][C:1](=[O:13])[NH:2][CH:20]([CH:21]1[CH2:16][CH2:15]1)[CH2:19][CH2:18][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:32][CH2:31]2)[C:23]1=[O:42])([CH3:9])([CH3:6])[CH3:5]
Reactant: BrCC1CCCCO1
Reactant: CC(C)(C)C1(OC(N)=O)CC1CBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: CC(C)(C)OC(=O)NC(CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)C1CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl-3-bromomethyl-1-cyclopropyl carbamate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-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, tert-butyl[1-cyclopropyl-3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]carbamate was obtained (91%) as a fluffy yellow solid: 1H NMR (300 MHz, CDCl3) δ7.28 (dd, J=7.7, 7.7 Hz, 1H), 7.13 (d, J=6.9 Hz, 1H), 7.02 (dd, J=7.2, 7.2 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.47 (s, 1H), 6.11 (d, J=4.9 Hz, 1H), 5.83 (d, J=5.5 Hz, 2H), 4.88 (dd, J=8.9, 7.0, Hz, 1H), 4.69 (br, 1H), 4.62 (dd, J=8.9, 1.7 Hz, 1H), 3.93-3.73 (m, 2H), 2.99 (br, 1H), 2.14-1.81 (m, 2H), 1.30 (s, 9H), 0.95-0.80 (m, 1H), 0.58-0.19 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.3, 177.3, 155.9, 155.7, 155.6, 148.8, 142.3, 142.2, 132.4, 129.0, 123.9, 123.3, 119.5, 119.4, 108.6, 103.1, 103.0, 101.5, 93.6, 80.4 (2C), 65.9, 58.2, 37.8, 37.5, 32.9, 32.7, 28.4, 16.1 (2C), 15.3, 3.9, 3.8, 3.0, 2.9; MS (ES+) m/z 501.3, (M+23), 479.28 (M+1), 423.2 (M−56), 379.3 (M−100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([N:15]([CH:18]([CH3:20])[CH3:19])CC)(C)C.[CH2:21]1COC[CH2:22]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:15][C:18]([CH3:19])([CH3:20])[CH2:21][CH3:22])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C1CCOC1
Product: CCC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (200 μL, 1.62 mmol) and tert-amyamine (170 mg, 1.95 mmol) in THF (5.0 mL) is added diisopropylethyl amine (500 μL, 2.87 mmol). The reaction mixture is allowed to cool to room temperature and is concentrated under reduced pressure to afford crude (4-bromo-2-nitro-phenyl)-(1,1-dimethyl-propyl)-amine (600 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[NH:27][C:26]3=[O:34])[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[C:26]3=[O:34])[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: Cc1c(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC(n3c(=O)n(CCN(C)C)c4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
To a stirred solution of 20 mg (0.043 mmol) of 1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (the preparation of which is described hereinafter) in DMF (3 ml) at RT, was added 2.0 mg (0.051 mmol) of NaH (60% in oil). The mixture was stirred 20 min. and then 5.6 mg (0.051 mmol) of (2-chloro-ethyl)-dimethyl-amine in 1 ml of DMF was added. The mixture was stirred an additional 5 hours at 50° C. and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (CH2Cl2/MeOH 8/2) afforded 12 mg (50%) of 1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-3-(2-dimethylamino-ethyl)-1,3-dihydro-benzoimidazol-2-one as a viscous oil. ES-MS m/e (%): 536.2 (M+H+).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:21]([OH:23])=[O:22])[C:15](=[CH:19][CH:20]=1)[C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:21](=[O:22])[O:23][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCCCOc2ccccc2)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(OCCCOc3ccccc3)ccc21

Procedure:
4-(3-phenoxypropoxy)phthalic acid (41g; 0.134 mole) was refluxed for 30 minutes with excess acetic anhydride and the product evaporated to dryness in vacuo. Recrysta lisation of the resulting white solid from ethyl acetate afforded material of m.p. 96°-98°. (Found, C, 68.48; H, 4.75; C17H14O5 requires; C, 68.45; H, 4.73%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]([Li])[CH2:8]CC.[C:12]([O:15][C:16]1[C:17]([CH3:30])=[C:18]([CH3:29])[C:19]2[O:23][C:22]([CH:25]=[O:26])([CH3:24])[CH2:21][C:20]=2[C:27]=1[CH3:28])(=[O:14])[CH3:13].O>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:12]([O:15][C:16]1[C:17]([CH3:30])=[C:18]([CH3:29])[C:19]2[O:23][C:22]([C:25](=[O:26])[CH:1]=[CH:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)([CH3:24])[CH2:21][C:20]=2[C:27]=1[CH3:28])(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(C=O)O2
Reactant: [Li]CCCC
Reactant: CCCCCC
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(C(=O)C=Cc1ccccc1)O2
Reaction time: 0.25 h

Procedure:
To a suspension of benzyltriphenyl phosphonium chloride [1.5 g (3.87 mmol)] in tetrahydrofuran (5 ml) was added dropwise, under ice-cooling, an n-butyl lithium hexane solution [(1.6M) 24 ml], followed by stirring for 15 minutes. To the reaction mixture was added a solution of 5-acetoxy-2-formyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (1.0 g) in tetrahydrofuran (3 ml). To the mixture was added water and it was subjected to extraction with ethyl acetate. The extract solution was washed with water and dried, then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography [hexane-IPE(2:1)] to obtain the desired 5-acetoxy-2-cinnamoyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (Compound 11) (1.22 g).
Reaction SMILES: [C:1]([C@@H:5]1[O:9][C:8](=[O:10])[C@H:7]([CH3:11])[O:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][C@:7]1([CH3:11])[O:6][C@@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][C:8]1=[O:10]
Reactant: C[C@@H]1O[C@H](C(C)(C)C)OC1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[C@H]1OC(=O)[C@](C)(Br)O1
Yield: 98 %

Procedure:
In 500 ml of carbon tetrachloride, 48.0 g of the (2S,5S)-2-tert-butyl-5-methyl-1,3-dioxolan-4-one obtained in Step 1 was dissolved. To the resulting solution, 54.0 g of N-bromosuccinimide and 1.0 ml of benzoyl peroxide were added, and the solution was refluxed for 2 hours. After the reaction solution was left to have cooled, insolubles were separated by filtration and the filtrate was successively washed with an aqueous 10% sodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated brine. From the filtrate thus washed, the carbon tetrachloride was evaporated under reduced pressure, and the resulting residue was recrystallized from hexane to obtain 70.5 g of (2S,5S)-5-bromo-2-tert-butyl-5-methyl-1,3-dioxolan-4-one.