Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(CN)CCCCC1.[O:16]=[C:17]1[C:25]2([CH2:29][O:28][C:27]3[CH:30]=[C:31]4[C:35](=[CH:36][C:26]2=3)[CH2:34][CH2:33][O:32]4)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:16]=[C:17]1[C:25]2([CH2:29][O:28][C:27]3[CH:30]=[C:31]4[C:35](=[CH:36][C:26]2=3)[CH2:34][CH2:33][O:32]4)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:43])=[CH:45][CH:46]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: Nc1ccccc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccccc1)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using aniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-phenylbenzamide was obtained (90%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.34 (s, 1H), 7.83 (d, J=7.8 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.39-7.23 (m, 4H), 7.23-6.97 (m, 4H), 6.72 (d, J=7.7 Hz, 1H), 6.44 (s, 1H), 6.38 (s, 1H), 4.92 (ABq, 2H), 4.77 (ABq, 2H), 4.48 (t, J=8.5 Hz, 2H), 2.89 (t, J=8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ178.1, 165.2, 161.8, 161.3, 141.6, 139.4, 137.9, 134.6, 132.4, 128.8, 128.7, 127.8, 127.4, 124.4, 123.9, 123.7, 120.2, 119.9, 119.7, 118.7, 109.1, 93.2, 80.4, 72.3, 57.7, 43.7, 28.8; MS (ES+) m/z 489.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7](C)[C:8]([O:10]CC)=[O:9].BrCCCCOCC(OCC)=O.O1CCCCC1[O:32][CH:33]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:34][CH2:35][CH2:36][N:37](CCCCOCC(OCC)=O)[S:38]([CH3:41])(=[O:40])=[O:39]>>[OH:32][C@H:33]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:34]#[C:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CCCCCC(CCCN(CCCCOCC(=O)OCC)S(C)(=O)=O)OC1CCCCO1
Reactant: CCOC(=O)C(C)CCCCCBr
Agent: CCOC(=O)COCCCCBr
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 8 except that, in Step A, the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of ethyl 4-bromobutoxyacetate (Example M). The product of Step A is thus ethyl 4-{N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamido}butoxyacetate. The subsequent step yields 4-[N-(4-hydroxynonyl)methanesulfonamido]butoxyacetic acid (B).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([NH:26][C@H:27]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[CH2:28][C:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31]([O:38][Si](C(C)(C)C)(C)C)[CH:30]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([NH:26][C@H:27]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[CH2:28][C:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31]([OH:38])[CH:30]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(O)ccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.4 ml (10.4 mmol) of a 1N tetrabutylammonium fluoride solution in THF are added to a solution of 2.77 g (5.22 mmol) of benzyl N-(tert-butoxycarbonyl)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-nitro-L-phenylalaninate (Example 5I) in 50 ml of THF, and the mixture is stirred at RT for 30 min. The solution is then poured into ice-water and extracted several times with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The crude product is dried to constant weight under high vacuum.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2>O.[Pt-]=O.CO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: OCc1ccc2ncccc2c1
Agent: O=[Pt-]
Solvent: CO
Solvent: O
Product: OCc1ccc2c(c1)CCCN2
Reaction time: 2 h
Yield: 68.7 %

Procedure:
6-Hydroxymethylquinoline (1 g, 6.28 mmoles) (prepared by the method of: C. E. Kaslow and W. R. Clark, J. Org. Chem., 1953, 18, 55-58.) and methanol (200 mL) were placed in a Parr bomb and platinum (I) oxide monohydrate (0.5 g, 2.04 mmoles) was added. The mixture was hydrogenated at 50 psi at 25° C. for 2 h. The catalyst was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 1.5% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (0.7044 g, 68%): CIMS: m/z 164.35 (MH+); 6. (CDCl3) 1.93 (2H, m, 3-CH2) and 2.76 (2H, t, 4-CH2), 3.30 (2H, m, 2-CH2), 4.50 (2H, s, CH2OH), 6.45 (1H, d, Ar—H8), 6.96 ppm (2H, m, Ar—H5 and Ar—H7); δC (CDCl3) CH2: 22.1, 27.0, 42.0, 65.6; CH: 114.2, 126.4, 129.2; C: 121.5, 129.4, 144.5.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].COC1C=CC(C[N:12]2[C:17]3[NH:18][N:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]=3[C:15](=[O:28])[N:14]([CH3:29])[C:13]2=[O:30])=CC=1.C1(OC)C=CC=CC=1>ClCCCl>[CH3:29][N:14]1[C:15](=[O:28])[C:16]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][NH:18][C:17]=2[NH:12][C:13]1=[O:30]
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Nc4ccccc4)n[nH]c32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: Cn1c(=O)[nH]c2[nH]nc(Nc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
AlCl3 (0.733 g, 5.50 mmol) is added to a solution of 7-(4-methoxybenzyl)-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.692 g, 1.83 mmol) and anisole (40 μL, 0.367 mmol) in 1,2-dichloroethane (10 mL) under argon. The reaction mixture is stirred at room temperature for 30 min, and then quenched with water with cooling. The resulting suspension is filtered through a layer of celite and the celite is washed with MeOH (20 mL). The product is eluted from the celite with a large amount of THF. The THF eluent is evaporated to afford 0.47 g of product (Yield: 99%). MS (FAB) m/z 258.2 [M+H]+.
Reaction SMILES: [Cl:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]([CH:12]=[CH2:13])=[O:11]>CCOC(C)=O.CC([O-])=O.[Na+]>[Cl:1][C:2]([C:8]#[N:9])([CH2:13][CH2:12][CH:10]=[O:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C#N
Reactant: C=CC=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)(C#N)CCC=O
Temperature: 35 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a suspension of NaOAc (0.492 g, 6 mmol) in 200 mL of EtOAc were added at 5° C., 31.0 g (210 mmol) of ethyl chlorocyanoacetate and acrolein (14 g, 250 mmol). The resulting mixture was stirred at 35° C. for 16 hours, filtered, concentrated and distilled to give 33 g of the title compound (77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[I-].[K+].[CH3:42][O:43][C:44](=[O:49])[CH2:45][CH2:46][CH2:47]Br>C1COCC1.O>[CH3:42][O:43][C:44](=[O:49])[CH2:45][CH2:46][CH2:47][N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([NH:18][C:16]2[C:17]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[C:10]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:20]1
Reactant: COC(=O)CCCBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NC4CCCNC4)c23)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCN1CCCC(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)C1

Procedure:
Heat a mixture of 100 mg (0.25 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-N-piperidin-3-yl-furo[2,3-d]pyrimidin-4-amine (Example 39A), 65 μl (0.375 mmol) of DIEA, 4.1 mg (0.025 mmol) of potassium iodide and 45 mg (0.25 mmol) of 4-bromobutyric acid methyl ester in 2 ml of THF under reflux for 1 h. After cooling, add the reaction mixture to water and extract three times with ethyl acetate. Wash the combined organic phases twice with buffer solution (pH 7) and saturated sodium chloride solution, dry over magnesium sulphate and concentrate under reduced pressure. Purify the crude product by preparative RP-HPLC (eluent: acetonitrile/water gradient), followed by chromatography on silica gel (eluent: dichloromethane→dichloromethane/methanol 50:1). After stirring the resulting product with methanol, the precipitate is filtered off with suction, washed with a little methanol and dried under high vacuum. 58 mg (46.4% of theory) of the target product are isolated.
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:4]2([CH3:5])[CH2:3]1)[C:16]1[CH:15]=[CH:14][C:13]([O:20][CH3:21])=[CH:12][C:11]=1[CH2:10][CH2:9]3.[N-:22]=[N+:23]=[N-:24].[Li+].O>CS(C)=O>[N:22]([C@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:4]2([CH3:5])[CH2:3]1)[C:16]1[CH:15]=[CH:14][C:13]([O:20][CH3:21])=[CH:12][C:11]=1[CH2:10][CH2:9]3)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@H](Br)C[C@@H]12
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@@H](N=[N+]=[N-])C[C@@H]12

Procedure:
A stirred solution of 1.56 g (4.5 mmol) 16α-bromo-3-methoxy-estra-1,3,5(10)-triene and 0.67 g (13.7 mmol) lithium azide in 30 ml of DMSO is heated for 1 h to 80° C. After cooling, water is added dropwise and the resulting precipitate is collected by filtration, washed with water and dried under vacuum. 1.33 g (96%). F=80-85° C., after recrystallization from ether/methanol: F=84-87° C. [α]D+60° (c=10.2).
Reaction SMILES: [C:1]1([Mg]I)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2I)[CH:13]=[CH:12][CH:11]=1>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[C:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Ic1cccc2cccc(I)c12
Reactant: I[Mg]c1ccccc1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Product: c1ccc(-c2cccc3cccc(-c4ccccc4)c23)cc1
Yield: 70 %

Procedure:
Nickel(II) acetylacetonate has affected other cross-coupling reactions, however. Mitchell and Yan, Can. J. Chem., 58, 2584 (1980), reported yields of 35-60%, 3,3"-dichloro-2,2"-dimethyl-o-terphenyl in the cross-coupling of 3-chloro-2-methylphenylmagnesium chloride with o-dibromobenzene in tetrahydrofuran using equivalent amounts of the reactants and 6 mole percent nickel(II) acetylacetonate based on the Grignard reagent. Ibuki, et al., Bull. Chem. Soc. Japan, 53, 821 (1980), reported cross-coupling two-fold excess phenylmagnesium bromide with 2-iodobiphenyl in the presence of 1.0% nickel(II) acetylacetonate based on the limiting reagent, obtaining a 78-80% yield of o-terphenyl. Clough, et al., J. Org. Chem., 41, 2256 (1976), reported cross-coupling an eight-fold excess of phenylmagnesium iodide with 1,8-diiodonaphthalene using 0.9 mole percent nickel(II) acetylacetonate based on the limiting reagent, producing 1,8-diphenylnaphthalene in 70% yield, while Corriu and Masse, J. Chem. Soc. Chem. Comm., 144 (1972), reported yields of 40 to more than 80% in cross-coupling reactions utilizing 0.1-1 percent nickel(II) acetylacetonate with respect to Grignard reagent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]([O:13][Si](C)(C)C)=[CH:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[F:25]OC(F)(F)F>ClC(Cl)(Cl)F>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([F:25])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: FOC(F)(F)F
Reactant: CN1C(O[Si](C)(C)C)=CN=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: FC(Cl)(Cl)Cl
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Yield: 108.8 %

Procedure:
A solution of 8.52 g of the aforesaid 7-chloro-1-methyl-5-phenyl-2-trimethylsiloxy-1H-1,4-benzodiazepine in 150 ml of trichlorofluoromethane was cooled to -70° C. and 2.4 g of trifluoromethyl hypofluorite were passed into the solution over a period of 3 hours. The reaction mixture then was warmed to room temperature and evaporated to dryness under reduced pressure to give 7.60 g of crude 7-chloro-3-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one as a light tan powder: mp 130°-140° C.; 19F NMR (CCl3D) δ-161.7 ppm (d,J=57 Hz).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:30]1C[CH:31]1[CH2:33][N:34]1[C:42]2[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=2[C:36]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=2)=[N:35]1>>[O:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:31]([OH:30])[CH2:33][N:34]3[C:42]4[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=4[C:36]([C:46]4[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=4)=[N:35]3)[CH2:13][CH2:12]2)=[N:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3ccccc23)CC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3noc4ccccc34)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A solution of 82 mg (0.27 mmol) of 4-benzo[d]isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester in 2 mL of CH2Cl2was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in EtOH and stirred over 100 mg of sodium bicarbonate for 1 h, the solid was then filtered off and the filtrate concentrated. The crude piperazine was then dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 105 mg (68%) of a white solid. MS (electrospray), exact mass calculated for C29H31F3N6O3, 568.24; m/z found, 569.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.77 (d, J=8.41 Hz, 1H), 7.69 (m, 2H), 7.67-7.62 (m, 2H), 7.50-7.44 (m, 1H), 7.45-7.42 (m, 1H), 7.23-7.18 (m, 1H), 4.93 (br m, 1H), 4.87 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.27-4.15 (m, 2.3H), 4.09-3.95 (m, 1.7H), 3.91-3.82 (m, 0.7H), 3.81-3.66 (m, 1.3H), 3.62-3.49 (m, 4H), 3.01-2.85 (m, 1.5H), 2.85-2.74 (m, 2.5H), 2.71-2.60 (m, 2H), 2.58-2.45 (m, 2H), 2.20 (s, 1.5H), 2.15 (s, 1.5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([N:16]([CH2:28][CH3:29])[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([CH3:27])[NH:24][CH2:23][CH2:22]2)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[C:17]([N:16]([CH2:28][CH3:29])[CH2:14][CH3:15])[CH:18]=[CH:19][CH:20]=4)[CH:25]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCN(CC)c1cccc2c1C(C)NCC2
Product: CCN(CC)c1cccc2c1C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-amine to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]=[N+:17]=[N-:18])[CH:9]=[C:8]([C:19]([O:21]CC)=[O:20])[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>O>[N:16]([CH2:15][CH2:14][CH2:13][O:12][C:10]1[CH:9]=[C:8]([C:19]([OH:21])=[O:20])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=1)=[N+:17]=[N-:18]
Reactant: CCOC(=O)c1cc(OCCCN=[N+]=[N-])cc(C(=O)OCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [N-]=[N+]=NCCCOc1cc(C(=O)O)nc(C(=O)O)c1
Temperature: 10 °C
Yield: 75 %

Procedure:
Diethyl-4-(3-azidopropoxy)-2,6-pyridinedicarboxylate, prepared above, (11.0 g, 34 mmol) was treated with a solution of sodium hydroxide (4.0 g, 0.10 mol) in water (120 mL) at 90-100° C. for 40 min. The reaction mixture was cooled to 10° C. and acidified to pH 1-2 with concentrated hydrochloric acid. The mixture was heated to dissolve the resulting white precipitate. Upon cooling 6.8 g (75%) of the title compound was obtained as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:22])=[CH:20][C:15]=3[N:14]=[CH:13]2)=[CH:8][CH:7]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][NH:23][C:21]([C:19]2[CH:18]=[CH:17][C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:37][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=5)=[CH:7][CH:8]=4)[CH:13]=[N:14][C:15]=3[CH:20]=2)=[O:22])[CH:26]=1
Reactant: Oc1ccccn1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OCCCOc2ccccn2)cc1
Temperature: 80 °C

Procedure:
1-[4-(3-Chloropropoxy)phenyl]-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (185 mg, 0.44 mmol), 2-pyridinol (42 mg, 0.44 mmol), cesium carbonate (156 mg, 0.48 mmol) and sodium iodide (72 mg, 0.48 mmol) were dissolved in DMF (4 mL) and the mixture heated at 80° C. under N2 for 16 h. After this time the reaction mixture was concentrated in vacuo and subjected to reverse-phase preparative HPLC purification to afford isolation of N-pyridin-3-ylmethyl-1-{4-[3-(pyridin-2-yloxy)propoxy]phenyl}-1H-benzimidazole-5-carboxamide; MS (ES+): m/z 480 [MH+] and 1-{4-[3-(2-Oxopyridin-1(2H)-yl)propoxy]phenyl}-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide; MS (ES+): m/z 480 [MH+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([F:13])([F:12])([F:11])([F:10])[F:9].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[CH:4][C:3]=1[S:8]([F:13])([F:9])([F:10])([F:11])[F:12]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccccc1S(F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(S(F)(F)(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
A mixture of 1-fluoro-2-(pentafluoro-λ6-sulfanyl)benzene (2.00 g, 9.00 mmol) and sulfuric acid (4 mL) was cooled in an ice bath. Nitric acid (4 mL) was added to the reaction mixture; after 5 minutes, the cooling bath was removed and stirring was continued at room temperature for 3 hours. The reaction mixture was then poured into ice (150 mL), and the resulting mixture was extracted with diethyl ether (2×75 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide an oil. After addition of a seed crystal, the product was obtained as a solid. Yield: 1.99 g, 7.45 mmol, 83%. 1H NMR (400 MHz, CDCl3) δ 7.45 (br dd, J=10, 9 Hz, 1H), 8.46 (br ddd, J=9.1, 3, 3 Hz, 1H), 8.72 (dd, J=5.8, 2.7 Hz, 1H).
Reaction SMILES: Br[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.[CH:21]([C:23]1[C:24]([O:32][CH3:33])=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH:21]=[O:22])[C:24]=2[O:32][CH3:33])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1c(C=O)cccc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc(C=O)c3OC)[nH]c2c1
Temperature: 110 °C
Yield: 77 %

Procedure:
Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as in International patent application WO 2004/087714), (3-formyl-2-methoxyphenyl) boronic acid (1.5 eq) and Pd(PPh3)2Cl2 (0.1 eq) were dissolved in dioxane (0.08M). The solution was degassed and flushed with Ar. 2M Na2CO3 solution (1 eq) was added and the mixture was heated to 110° C. for 2 h. All volatiles were evaporated in vacuo and the residual material was dissolved in EtOAc, filtered over Celite and evaporated in vacuo. The residual material was filtered over a plug of silica gel eluting with (PE/EtOAc 1:1). After evaporation of the fractions containing product and trituration with Et2O methyl 3-cyclohexyl-2-(3-formyl-2-methoxyphenyl)-1H-indole-6-carboxylate was obtained as off-white solid (77%). (ES+) m/z 392 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>CCOCC>[CH3:1][N:2]1[C:6]([C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:25][CH:24]=2)=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Solvent: CCOCC
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n1C
Yield: 84.8 %

Procedure:
A solution of 7.24 g (0.04 mole) of ethyl 1,4-dimethylpyrrole-2-acetate and 11.1 g (0.06 mole) of p-nitrobenzoyl chloride in 30 ml of ether under argon is stirred at room temperature in the dark for two days. The precipitate is collected by filtration. Recrystallization from isopropanol gives 11.2 g (85% yield) of ethyl 1,4-dimethyl-5-(p-nitrobenzoyl)pyrrole-2-acetate as yellow crystals, m.p. 148°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][N:13]([C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])[C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Product: O=C(c1ccccn1)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 29 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and pyridine-2-carbonyl chloride hydrochloride as the starting materials in 29% yield. LCMS for C23H18ClN6O (M+H)+: m/z=429.0.
Reaction SMILES: C1(C)C=CC(S([O-])=O)=CC=1.[Na+].[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](C=O)=[C:15]1[CH3:25])[CH3:13]>>[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH3:25])[CH3:13]
Reactant: CCn1c(C)c(C=O)c2ccccc21
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: CCn1c(C)cc2ccccc21

Procedure:
Following a procedure similar to that described in Example 4A but employing 6.5 g. of 85.9% sodium p-toluenesulfinate, 4.6 g. of 1-ethyl-2-methyl-1H-indole-3-carboxaldehyde and 3.8 g. of 1-ethyl-2-methyl-1H-indole there was obtained 4.5 g. of 3-[(1-ethyl-2-methyl-1H-indol-3-yl)(4-methylphenylsulfonyl)methyl]-1-ethyl-2-methyl-1H-indole, m.p. 146°-152° C.