Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH2:43][CH2:44][O:45][CH2:46][CH3:47])[CH3:42])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:46]([O:45][CH2:44][CH2:43][N:41]([C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1)[CH3:42])[CH3:47]
Reactant: CCOCCN(C)c1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-[N-(2-ethoxyethyl)-N-methylamino]phenyl borate (168 mg) and potassium carbonate (176 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give yellow crystals of 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 70) (235 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CCC3)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Tert-butyl(±)-cis-2-(2,3-dichlorophenyl)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (55 mg, 0.12 mmol) was dissolved in 20% TFA in methylene chloride (4 mL) and was stirred at RT for 2 h. The reaction was solution was cooled to 0° C. and basified with 1 M NaOH until pH >14. The layers were separated. The aqueous phase was extracted the methylene chloride (2×10 ml). The organic layers were washed with brine and dried. Concentration afforded the title compound (43 mg, 100%) as a pale yellow amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.37 (dd, 1H, J=2.6, 7.3 Hz), 7.15–7.23 (m, 2H), 6.97 (s, 1H), 6.92 (s, 1H), 3.43–3.46 (m, 1H), 3.31 (dt, 1H, J=4.4, 10.2), 3.03–3.11(m, 2H), 2.81–2.94 (m, 2H), 2.60–2.80 (m, 4H), 2.11–2.20 (m, 2H), 1.89–1.98 (m, 1H), 1.74–1.85 (m, 1H) ppm. MS (CI, NH3): 359 (base, M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[S:3])[NH2:2].[C:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23](=O)[CH2:24]Br)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=3)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3][CH:24]=2)=[CH:27][CH:28]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1cccc(C(N)=S)c1
Reactant: CC(C)(C)c1ccc(C(=O)CBr)cc1
Product: CCOC(=O)c1cccc(-c2nc(-c3ccc(C(C)(C)C)cc3)cs2)c1
Yield: 37 %

Procedure:
In the same manner as in Example 74, ethyl 3-thiocarbamoylbenzoate was reacted with 4-t-butylphenacyl bromide to obtain ethyl 3-[4-(4-t-butylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 37%. Pale yellow prisms. Melting point: 96 to 97° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH2:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(O)(=O)C>CO.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH2:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(C)C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN

Procedure:
In 50 ml of MeOH is dissolved 350 mg of Z-Tyr-(D)-Leu-Gly-Phe-NH-NH2, and following addition of 0.1 ml of acetic acid, catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filteredoff, the filtrate is concentrated and the residue is dissolved in a small amount of 1N-aqueous acetic acid and put on a column of Sephadex LH-20(2.5×120 cm). Elution is carried out with 1 N-aqueous acetic acid and fractions from 320 through 340 ml are collected and lyophilized. 210 mg (60%); [α]D22 +22.6° (c=0.38, MeOH); Rf2 =0.34; amino acid analysis (acid hydrolyzate): Gly, 1.00, Leu, 1.00; Tyr, 0.90; Phe, 1.02; mean recovery rate 70%.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([CH3:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[CH:3][C:4]=2[CH3:19])[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cc(N)ccc1Oc1ccnc(N)c1[N+](=O)[O-]
Product: Cc1cc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)ccc1Oc1ccnc(N)c1[N+](=O)[O-]
Yield: 143.4 %

Procedure:
Method H3 was used with 4-(4-amino-2-methylphenoxy)-3-nitropyridin-2-amine (0.22 g, 0.991 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.16 g, 0.709 mmol) to afford the title compound (0.49 g, 100%). 1H NMR (250 MHz, 6, ppm, DMSO-d6): 2.10 (s, 3H), 5.81 (d, 1H, J=5.7 Hz), 7.08 (d, 1H, J=8.7 Hz), 7.14 (s, 2H), 7.37 (dd, 1H, Ja=8.8 Hz, Jb=2.6 Hz), 7.49 (d, 1H, J=2.4 Hz), 7.58-7.66 (m, 2H), 7.96 (d, 1H, J=5.7 Hz), 8.12 (d, 1H, J=2.1 Hz), 8.89 (s, 1H), 9.16 (s, 1H). m/z 482.1 [(M+H)+ calcd. for C20H15ClF3N5O4 481.1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](C(O)CC)[CH:2]=1.[C:11]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=CC=C[CH:12]=1.C(Cl)(Cl)(Cl)[Cl:31]>C1COCC1>[N:1]1[CH:2]=[CH:3][C:4]([CH2:12][CH2:11][CH2:16][Cl:31])=[CH:5][CH:6]=1
Reactant: CCC(O)c1cccnc1
Reactant: ClC(Cl)(Cl)Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCCc1ccncc1
Reaction time: 24 h

Procedure:
A solution of 3-pyridylpropanol (2-2) (ICN Biochemicals, 14.2 g, 0.1 mol) in THF (200 mL) was treated successively with triphenylphosphine (47.2 g, 0.18 mol) and carbontetrachloride (17.4 mL, 0.18 mol) and stirred for 24 h. The reaction was filtered and the solids washed with Et2O. The filtrate was concentrated to give a yellow solid which was triturated with Et2O. Chromatography (silica gel, 30% EtOAc/Hexanes) gave 2-3 as yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1>Cl>[ClH:9].[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Product: CN(c1ccccc1)c1ncccc1[N+](=O)[O-]
Yield: 66.5 %

Procedure:
To 59 g (0.55 mole) of N-methylaniline, stirred and heated at 115°-120° C. under nitrogen atmosphere was added 79 g (0.50 mole) of 2-chloro-3-nitropyridine in four portions at 15 minute intervals. The melt was maintained at 120°-125° C. for 1 hour and then poured into 700 ml of dilute aqueous hydrochloric acid. The precipitate was collected by filtration and dried. The solid was dried and recrystallized as the hydrochloride salt from ethyl acetate-ethereal hydrogen chloride to give 88.3 g (66%) yellow solid. A portion was recrystallized from ethyl acetate-ethyl alcohol to give yellow solid, m.p. 181°-182° C. after undergoing phase changes from 165°-170° C. and at 179° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:5]=2[CH:6]=1.N[C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][N:25]=1.P(Cl)(Cl)(Cl)=O.O.N1C=CC=C[CH:41]=1>>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11](=[O:13])[NH:25][C:24]3[CH:41]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:29]=3)[CH:8]=[C:7]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:5]=2[CH:6]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1cc2c(OCc3ccccc3F)cc(C(=O)O)cc2o1
Reactant: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3F)c3cc(C)oc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of 2-methyl-4-(2-fluorobenzyloxy)-1-benzofuran-6-carboxylic acid (Method 3; 0.60 mg, 0.2 mmol) and methyl 2-aminopyridine-5-carboxylate (61 mg, 0.4 mmol, 2 eq) in pyridine (1 ml) was treated with phosphorus oxychloride (20.5 μl, 0.22 mmol, 1.1 eq), and the reaction mixture stirred for 16 hrs at ambient temperature. The reaction mixture was poured into water and extracted twice with ethyl acetate; the extracts were washed with brine, dried (MgSO4) and evaporated to give a yellow gum. This was chromatographed (10 g Bondelut, eluting with hexane containing ethyl acetate, 0-100%) to give the title compound as a solid (61 mg, 70%). NMR: 2.46 (s, 3H), 3.87 (s, 3H), 5.37 (s, 2H), 6.66 (s, 1H), 7.25 (m, 2H), 7.42 (m, 1H), 7.62 (m, 2H), 7.91 (s, 1H), 8.36 (m, 2H), 8.91 (s, 1H), 11.20 (bs, 1H); m/z 435 (M+H)+, 100% by LC-MS.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[CH2:21]([NH2:30])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:30][CH2:21]/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NC/C=C/c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1csc2c(NC/C=C/c3ccccc3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To 10 ml of a solution of 438 mg (2.0 mmol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 339 mg (2.0 mmol) of trans-cinnamylamine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 341 mg (yield: 54.0%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].BrBr.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>O1CCOCC1.C(#N)C>[CH3:14][C:15]1[N:16]([CH2:2][C:1]([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])=[O:3])[CH:17]=[CH:18][N:19]=1
Reactant: Cc1ncc[nH]1
Reactant: CC(=O)c1cccc(C#N)c1
Agent: BrBr
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1nccn1CC(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-acetylbenzonitrile (50 g, 0.345 mol) is dissolved in dioxane (600 ml) with stirring at room temperature, bromine (17.7 ml, 0.345 mol) is added in and the mixture is stirred for 30 minutes. The dioxane is removed in vacuo to give a solid which is dissolved in acetonitrile (300 ml). 2-Methylimidazole (28.3 g, 0.345 mol) is added to the solution and the mixture is stirred for 1 hour, the temperature of the mixture rising to 45° C. The precipated solid is filtered off, washed with acetonitrile, and slurried with methanol for 1 hour. After filtering to remove undissolved solid, the filtrate is evaporated in vacuo to leave a solid which is dried in vacuo at 40° C. to give the title compound, m.s. 369 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[C:11]([CH3:12])[C:3]=12.[H-].[Na+].FC(F)(F)S(O[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[N:9]([Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:10]=[C:11]([CH3:12])[C:3]=12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1c[nH]c2c(Cl)ncc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cn([Si](C)(C)C(C)(C)C)c2c(Cl)ncc(Br)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-7-chloro-3-methyl-1H-pyrrolo[2,3-c]pyridine (1.07 g) in dry tetrahydrofuran (50 ml) at 0° C. under an atmosphere of nitrogen was added portionwise sodium hydride (60% dispersed in mineral oil, 384 mg). After addition, the solution was stirred at room temperature for 30 minutes. The solution was then recooled to 0° C. and a solution of tert-butyldimethylsilyl trifluoromethanesulphonate (2 ml) in dry tetrahydrofuran (10 ml) was added dropwise. The solution was stored at 5° C. overnight. The solution was partitioned between ethyl acetate and water and washed with water twice. The organic layer was dried (MgSO4) and evaporated to give a brown oil (2 g). The residue was used in the next step (d) without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7](O)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([C:7]1[C:2]([Br:1])=[N:3][C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1)(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1ccc([N+](=O)[O-])nc1Br

Procedure:
Starting materials 3-acetyl-6-amino-2-bromopyridine and 2-(2-chloro-3-ethoxy-6-fluorophenyl)-cyclopropylisocyanate, were prepared in following manner: 5 g of 2-Bromo-3-pyridinol (Aldrich) was added to a mixture of 25 ml of conc. H2SO4 and 25 ml of fuming HNO3 at 0° C. The mixture was stirred one hour at that temperature, then added to 350 ml of crushed ice and extracted with CH2Cl2. The extract was dried with Na2SO4 and evaporated in vacuo to yield 4.1 g of a crude product as a mixture of 2-bromo-6-nitro-3-pyridinol and 2-bromo-4,6-dinitro-3-pyridinol. The mixture (0.5 g) was treated with an excess of acetic anhydride at room temperature at 24 hours, then separated on a silica-gel column eluated with mixtures of hexane and ethylacetate to yield 0.28 g of 2-bromo-6-nitro-3-pyridinol as a yellowish solid. 2-Bromo-6-nitro-3-pyridinol was then treated with acetic anhydride at 80° C. at 14 hours under an atmosphere of nitrogen to yield 0.34 g of 3-acetyl-2-bromo-6-nitropyridine as a yellow solid. Hydrogenation of 3-acetyl-2-bromo-6-nitropyridine in ethanol (Pt on C, 1 atm) gave 3-acetyl-6-amino-2-bromopyridine as a reddish oil. The cis/trans mixture of 2-(2-chloro-3-ethoxy-6-fluorophenyl)cyclopropylisocyanates were prepared from 2-chloro-4-fluorophenol (Aldrich) in manner analogous to Examples 362, 375 and 348 of WO 93/03022. This product was then condensed with 3-acetyl-6-amino-2-bromopyridine in a manner analogous to the method in Example 7 to provide cis/trans mixture of N-2-(2-Chloro-3-ethoxy-6-fluorophenyl)-cyclopropyl-N'-(6-bromo-5-hydroxypyrid-2-yl)-ureas. The two products were separated on a silica-gel column eluated with mixtures of hexane and ethylacetate to yield the titled compound as a white solid: 1H NMR (250 MHz, CDCl3) δ 7.85 (d, 1H), 7.55 (br s, 1H), 6.98-6.72 (m, 2H), 4.04 (q, 2H), 3.27-3.04 (m, 1H), 2.18 (q, 1H), 1.74-1.65 H (m, 1H), 1.43 (t, 3H), 0.92-0.80 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([CH2:10][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>CN(C=O)C>[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:9]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=3[N:7]=[C:8]2[CH2:10][C:11]([CH3:17])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:30][CH:29]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:7]2[C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][C:11]([CH3:17])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:30][CH:29]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OC)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1nc2cc(OC)ccc2n1Cc1ccc(Br)cc1
Product: CCOC(=O)C(C)(C)Cc1nc2ccc(OC)cc2n1Cc1ccc(Br)cc1
Reaction time: 12 h
Yield: 23 %
Yield: 26 %

Procedure:
To a 100 mL round-bottomed flask were added a stir bar, ethyl 3-(5-methoxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (1.5 g, 5.4 mmol), DMF (19 mL), cesium carbonate (3.5 g, 11 mmol), and 4-bromobenzyl bromide (1.4 g, 5.4 mmol). After 12 h, the mixture was partitioned between water (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were dried with sodium sulfate, filtered, and concentrated to dryness. The residue was subjected to FCC to give ethyl 3-(1-(4-bromobenzyl)-6-methoxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (550 mg, 23%) and ethyl 3-(1-(4-bromobenzyl)-5-methoxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (620 mg, 26%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)O)[CH:5]=[CH:6][CH:7]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C(O)c2cccc(O)c2)c1
Reactant: c1nc[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cccc(C(c2cccc(O)c2)n2cncn2)c1
Yield: 88.4 %

Procedure:
Bis-(3-hydroxyphenyl)methanol (0.75 g, 3.47 mmol), 1,2,4-triazole (0.48 g, 6.94 mmol), p-TSA (125 mg) and toluene (300 mL) were dissolved/suspended in toluene and heated at reflux with a Dean-Stark separator for 24 h. The reaction mixture was allowed to cool, and the solvent was removed in vacuo. The resulting residue was dissolved in EtOAc (75 mL) and the organic layer was washed with H2O (3×75 mL), dried (MgSO4) and the solvent was removed in vacuo to give a brown solid. The crude product was purified by flash column chromatography (EtOAc:Hexane 3:1) to give the title compound (0.82 g, 88%) as a pale yellow oil which formed a foam after a prolonged period under high vacuum; δH (270 MHz, d6-DMSO) 9.50 (2H, br s, ArOH), 8.55 (1H, s, NCHN), 8.06 (1H, s, NCHN), 7.16 (2H, t, J=7.9, ArH), 6.89 (1H, s, CH), 6.75-6.68 (2H, m, ArH), 6.67-6.60 (4H, m, ArH); δC (100 MHz, d6-DMSO) 158.0 (2×C), 152.3 (CH), 144.9 (CH), 141.0 (2×C), 130.2 (2×CH), 119.3 (2×CH), 115.6 (2×CH), 115.6 (2×CH), 66.2 (CH); LRMS (FAB+) 268.3 ([M+H]+, 100%), 199.2 (85); HRMS (FAB+) Found 268.1091, C15H14N3O2 requires 268.1086; HPLC (CH3CN/H2O, 90:10) tR=1.79 min (purity: 99+%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].C([Li])CCC.[Br:16][C:17]1[CH:18]=[C:19]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:21]1([CH2:23][CH2:22]1)[C:20]2=[N:29]S(C(C)(C)C)=O.[NH4+].[Cl-]>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]2[C:20]3([C:6]4[C:3](=[C:2]([F:1])[CH:9]=[CH:8][CH:7]=4)[C:4]([NH2:5])=[N:29]3)[C:21]3([CH2:22][CH2:23]3)[CH2:24][O:25][C:26]2=[CH:27][CH:28]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2OCC12CC2
Reactant: N#Cc1c(F)cccc1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC1=NC2(c3cc(Br)ccc3OCC23CC3)c2cccc(F)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of 2-fluoro-6-iodobenzonitrile (1560 mg, 6.32 mmol) in THF (16 mL) at −78° C. was added n-butyllithium (2.64M solution in n-hexane, 2.39 ml, 6.32 mmol) dropwise. The mixture was stirred for 0.5 hour at −78° C. and to the solution was added a solution of N-(6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-ylidene)-2-methylpropane-2-sulfinamide (1500 mg, 4.21 mmol) in THF (5 mL). The mixture was stirred for 1 hour at −78° C. and overnight at room temperature. To the mixture was added saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/AcOEt=100:0-0:100, then CHCl3:MeOH=85:15) to give 6′-bromo-4″-fluorodispiro[cyclopropane-1,3′-chromene-4′,1″-isoindol]-3″-amine (469 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:32][C:29]([CH3:30])([CH3:31])[C:28](=[O:33])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]([C:9]2[CH:8]=[C:7]3[C:12]([CH:13]=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[CH:6]3)=[CH:11][CH:10]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:34]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2ccc(C(=O)OC)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2ccc(C(=O)O)cc2c1
Temperature: 55 °C
Yield: 89.6 %

Procedure:
Treat 7-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carboxylic acid methyl ester (1.1 g, 2.4 mmol) in THF (15 mL) and MeOH (30 mL) with 2N NaOH (6.0 mL, 12.0 mmol) and heat to 55° C. for 16 h. Then concentrate the reaction mixture and dilute the residue with CH2CL2 and water (50 mL each). Acidify the mixture to pH 1 using 1N HCl. Discard the aqueous layer and wash the organic layer with brine. Dry the organic layer over Na2SO4, filter and concentrate the filtrate. Purify by silica gel radial chromatography (2:98 MeOH:CH2CL2 to 10:90 MeOH:CH2CL2) to give the title compound as a yellow solid (0.96 g, 90%). MS (ES) m/e 447 (M+1).