Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:21]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br)([O-:23])=[O:22].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[N+:21]([O-:23])=[O:22])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: O=[N+]([O-])c1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1[N+](=O)[O-]
Yield: 89.5 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.431 g, 1.61 mmol), 2-nitrobenzyl bromide (0.509 g, 2.75 mmol),KI (60 mg, 0.36 mmol), and DIPEA (0.6 mL, 3.44 mmol) in DMF (8 mL) was heated at 60° C. for 24 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.58 g (90%) of COMPOUND 64 as a yellow solid. 1H NMR (CDCl3) δ 1.63-1.70 (m, 3H), 2.04-2.08 (m, 1H), 2.31-2.43 (m, 8H), 3.85 (s, 2H), 4.12 (d, 2H, J=11.1 Hz), 6.83-6.91 (m, 3H), 7.18-7.29 (m, 4H), 7.78 (d, 1H, J=7.5 Hz), 8.24 (d, 2H, J=3.9 Hz); ES-MS m/z 403 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc([C@H](C)c2nccn2C(=O)OCC(C)C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the compound of Example 58 (1.00 g, 5.0 mmol) and triethylamine (0.77 ml, 5.5 mmol) in anhydrous dichloromethane (10 ml) was added dropwise isobutyl chloroformate (2.60 ml, 20 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].Br[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([O:17][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(O)c2cccc(O)c2oc1=O
Reactant: CCOC(=O)CCBr
Product: CCCCOc1c(O)c2cccc(OCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-butoxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-butoxy-4-hydroxy-8-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20].Cl>CC(C)=O.O>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([I:3])=[CH:15][CH:14]=1)=[O:20]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(N[C@@H](Cc1ccc(I)cc1)C(=O)O)c1c(Cl)cccc1Cl
Temperature: 10 °C

Procedure:
Water (21 mL), acetone (9.80 mL) and a 6M sodium hydroxide aqueous solution (5.20 mL) were added to 7.50 g of 4-iodo-L-phenylalanine and the resulting mixture was stirred at 10° C. to thus give a uniform solution. To this solution, there were alternatively added 4.05 mL of 2,6-dichlorobenzoyl chloride and 4.50 mL of a 6M sodium hydroxide aqueous solution while taking care to maintain the pH value of not less than 13 and the temperature of not higher than 15° C. After confirming the completion of the reaction, 6.50 mL of a 6M hydrochloric acid aqueous solution was added to the reaction system to thus precipitate the desired product. The solid thus separated was isolated through filtration under reduced pressure, washed with 15 mL of water and dried at 70° C. for 4 hours under reduced pressure to thus give 12.42 g of the intended product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([F:15])[CH:4]=1)[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][C:32](Cl)=[O:33])[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24].Cl>ClCCl>[CH2:20]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][C:32]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=3[F:15])=[CH:14][CH:13]=2)=[O:33])[CH2:29][CH2:30]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC[C@H]1CC[C@H](CC(=O)Cl)CC1
Reactant: CCc1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CC(=O)c2ccc(-c3ccc(CC)cc3F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Ethyl-2-fluorobiphenyl (13.0 gram) was added in one portion to a stirred suspension of aluminium trichloride (9.54 gram) in dichloromethane (30 ml), followed by a solution of trans-4-n-pentylcyclohexyl acetyl chloride (15 gram) in dichloromethane (30 ml), added dropwise over 30 minutes. After stirring at room temperature for 31/2 hours, the reaction mixture was poured onto ice (250 gram) and hydrochloric acid (25 ml) and the product was extracted with 350 ml and 250 ml portions of petroleum ether (boiling point 60°-80° C.). The combined extracts were washed with water (150 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue (26.8 gram) was crystallised from industrial methylated spirits at 0° C. to give 13.2 gram (51.5% yield) 4-(trans-4-n-pentylcyclohexylacetyl)-2'-fluoro-4'-ethylbiphenyl, melting point 72°-73° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.Br[C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:27]([CH2:34][O:35][CH2:36][CH3:37])=[N:26][C:20]=3[C:21]([NH2:25])=[N:22][C:23]=2[CH:24]=1.N[C@@H]1CCCC[C@H]1N>[Cu]I.O1CCOCC1>[CH2:36]([O:35][CH2:34][C:27]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([N:9]4[CH:13]=[CH:12][CH:11]=[N:10]4)=[CH:24][C:23]=3[N:22]=[C:21]([NH2:25])[C:20]=2[N:26]=1)[CH3:37]
Reactant: c1cn[nH]c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOCc1nc2c(N)nc3cc(-n4cccn4)ccc3c2n1CCCOC
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 25 %

Procedure:
A 4 dram vial containing a stir bar was charged sequentially with copper(I) iodide (0.038 g), potassium phosphate (0.890 g), pyrazole (0.164 g), 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.786 g), (±)-trans-1,2-diaminocyclohexane (0.030 mL), and anhydrous 1,4-dioxane (2 mL). The vial was flushed with nitrogen, capped, and placed in an oil bath at 110° C. After 15.5 hours, the reaction was cooled to room temperature and purified by flash column chromatography using a gradient of CMA/chloroform as the eluent. Subsequent recrystallization from acetonitrile yielded 0.190 g of 2-ethoxymethyl-1-(3-methoxypropyl)-7-(pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 159.0–160.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.OO.C=CCCCC.C(=O)([O-])[O-:32].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21](=[O:32])[NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C=CCCCC
Product: NC(=O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
50 mg (0.16 mmol) of N-(3-chloro-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine are suspended in 2 ml of methanol. 0.58 ml of hydrogen peroxide (30% strength), 0.16 ml of 1-hexene and 11 mg of sodium carbonate are added and the reaction mixture is stirred for 14 hours at RT. The product is isolated by filtration, washed (methanol:water=1:1) and dried at 50° under HV. N-(3-chloro-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine is obtained in the form of a yellow powder; m.p. 245°-247°, Rf =0.23 (n-hexane:ethyl acetate=1:1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Li]CCCC.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1
Reactant: CCCCCCCBr
Reactant: Cc1cc(C)c2c(n1)N(C)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1cc(C)c2c(n1)N(C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing −490 mg (2.71 mmol) of 1,4,6-Trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 7.2 mL of THF was added 2.70 mL (4.34 mmol) of n-BuLi (1.6 M in hexanes) followed by 4504 (509 mg, 2.85 mmol) of 1-bromoheptane at −78° C. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched by the addition of 25 mL of sat aq. NH4Cl at 0° C. The mixture was extracted with three 40-mL portions, of EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica gel column (42×2.5 cm). Step gradient elution with 1:10→1:4 ethyl acetate-hexanes as eluent gave 1,4-dimethyl-6-octyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine as a yellow oil: yield 402 mg (57%); silica gel TLC Rf 0.36 (8:1:1 hexanes-ethyl acetate-methanol); 1H NMR (CDCl3) δ 0.79 (t, 2H, J=7.2 Hz), 1.16-1.30 (m, 10H), 1.58 (quint, 2H, J=8.0 Hz), 2.00 (s, 3H), 2.48 (t, 2H, J=8.0 Hz), 2.72 (t, 2H, J=8.4 Hz), 2.82 (s, 3H), 3.38 (t, 2H, J=8.4 Hz), 6.14 (s, 1H).
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[NH:25][CH:24]([CH2:26][C:27]([O:29]C)=[O:28])[C:23](=[O:31])[N:22]([CH3:32])[CH2:21][C:20]=2[CH:33]=1)=[O:15]>C1COCC1.CO>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[NH:25][CH:24]([CH2:26][C:27]([OH:29])=[O:28])[C:23](=[O:31])[N:22]([CH3:32])[CH2:21][C:20]=2[CH:33]=1)=[O:15]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3cc4ccccc4[nH]3)cc2CN(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1Cc2cc(C(=O)NCc3cc4ccccc4[nH]3)ccc2NC(CC(=O)O)C1=O
Reaction time: 20 h
Yield: 29.6 %

Procedure:
1.0 N NaOH (1 mL, 1.0 mmol) was added dropwise to a solution of methyl (±)-7-[[[(2-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.35 g, 0.83 mmol) in THF (5 mL) and MeOH (2 mL) at RT. The resulting mixture was stirred for 20 h then was concentrated. The residue was dissolved in H2O (20 mL) and acidified with TFA. ODS chromatography (27% CH3CN/H2O-0.1% TFA), concentration and lyophilization gave the title compound (100 mg, 30%) as an off-white solid: HPLC (ODS, 5-60% CH3CN/H2O-0. 1% TFA gradient elution over 20 min) K'=10.2; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (t, 1H), 7.57 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 7.33 (d, 1H), 7.01 (t, 1H), 6.93 (t, 1H), 6.55 (d, 1H), 6.33 (br, 1H), 6.25 (s, 1H), 5.49 (d, 1H), 5.08 (t, 1H), 4.55 (d, 2H), 3.82 (d, 1H), 2.92 (s, 3H), 2.75 (dd, 1H), 2.53 (d, 1H); MS (ES) m/e 407.2(M+H)+. Anal. Calcd for C22H22N4O4.H2O: C, 62.25; H, 5.70; N, 13.20. Found: C, 62.66; H, 5.64; N, 12.99.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:33]1[C:34]2[C:35]3[CH:48]=[CH:47][S:46][C:36]=3[C:37](=[O:45])[NH:38][C:39]=2[CH:40]=[CH:41][C:42]=1[O:43][CH3:44]>>[CH3:44][O:43][C:42]1[CH:41]=[CH:40][C:39]2[NH:38][C:37](=[O:45])[C:36]3[S:46][CH:47]=[CH:48][C:35]=3[C:34]=2[C:33]=1[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: Cc1cc(Br)ccc1NS(C)(=O)=O
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(NS(C)(=O)=O)c(C)c1
Yield: 27.3 %

Procedure:
Following General Procedure E, N-(4-bromo-2-methylphenyl)methanesulfonamide (130 mg, 0.50 mmol) was reacted with bis(pinacolato)diboron (140 mg, 0.55 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (140 mg, 0.45 mmol) to afford the desired product (51 mg, 27%) as a brown solid: ESI MS m/z 415 [C20H18N2O4S2+H]+.
Reaction SMILES: C(OC(=O)C1C=CC(CC2ON=C(CO)N=2)=CC=1)C.[CH2:20]([O:22][C:23](=[O:46])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][C:31]2[O:35][N:34]=[C:33]([CH2:36][O:37]C3C=CC(OC)=CC=3)[N:32]=2)[CH:25]=1)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:46])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][C:31]2[O:35][N:34]=[C:33]([CH2:36][OH:37])[N:32]=2)[CH:25]=1)[CH3:21]
Reactant: CCOC(=O)c1cccc(Cc2nc(COc3ccc(OC)cc3)no2)c1
Agent: CCOC(=O)c1ccc(Cc2nc(CO)no2)cc1
Product: CCOC(=O)c1cccc(Cc2nc(CO)no2)c1

Procedure:
The title compound is prepared essentially as described for 4-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester, employing 3-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester (81%). LC-MS (m/e): 263 (M+1).
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:11]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]([O:19][C:20]2[N:21]=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:28][C:27]=3[O:37]C)=[CH:24][CH:25]=2)[CH2:12]1)[CH3:10])(C(C)(C)C)(C)C.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C@H:9]([C@H:11]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]([O:19][C:20]2[N:21]=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:28][C:27]=3[OH:37])=[CH:24][CH:25]=2)[CH2:12]1)[CH3:10]
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(OC2C[C@@H]([C@H](C)O[Si](C)(C)C(C)(C)C)NC(C)(C)C2)nn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](O)[C@@H]1CC(Oc2ccc(-c3ccc(-n4cccn4)cc3O)nn2)CC(C)(C)N1
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 3-((6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-yloxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine (56 mg, 0.1 mmol) in CH2Cl2 (2 mL) was added BBr3 (1 M in heptane, 0.13 mL, 0.13 mmol) dropwise at 0° C. The mixture was stirred overnight. The reaction mixture was quenched with water and then basicifed with saturated NaHCO3 solution. The organic layer was extracted with 10% MeOH in dichloromethane (10 mL×3). The combined extracts were dried over Na2SO4 and concentrated in vacuo. Purification by HPLC gave 12 mg (28%) of 2-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol: LCMS Rt=0.52 min (LCMS method Q); MS=410.3 (M+1); 1H NMR (400 MHz, METHANOL-d4) δ 8.23 (d, J=9.6 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.32-7.25 (m, 2H), 7.22 (d, J=9.6 Hz, 1H), 6.47-6.43 (m, 1H), 5.59-5.66 (m, 1H), 3.68-3.77 (m, 1H), 3.02-3.11 (m, 1H), 2.03-2.15 (m, 2H), 1.49-1.59 (m, 2H), 1.24 (s, 3H), 1.11 (d, J=6.4 Hz, 3H), 1.10 (s, 3H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([C:25]3[CH:30]=[N:29][CH:28]=[C:27](I)[N:26]=3)=[N:22][C:21]=2[CH3:32])=[O:19])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[F:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([C:25]3[CH:30]=[N:29][CH:28]=[C:27]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:26]=3)=[N:22][C:21]=2[CH3:32])=[O:19])=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1nc(-c2cncc(OCc3ccccc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of benzyl alcohol (25 μL, 0.24 mmol) in dimethyl acetamide (0.5 mL) in the sealed tube was added NaH (10.4 mg, 0.26 mmol). The reaction mixture was stirred at room temperature. After 30 min, a solution of 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (100 mg, 0.22 mmol) and diisopropyl ethylamine (96 μL, 0.55 mmol) was added to the reaction mixture. The reaction mixture was stirred at 100° C. After 12 hr, the reaction mixture was cooled to room temperature, quenched with methanol, diluted with CH2Cl2, washed with water and brine, then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound in 60% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.92 (s, 1H), 8.29 (s, 1H), 7.47-7.51 (m, 2H), 7.31-7.40 (m, 5H), 7.02-7.08 (m, 2H), 6.20 (bs, 1H), 5.44 (s, 2H), 4.57 (d, J=8.0 Hz, 2H), 2.72 (s; 3H); MS (ES+) m/z 435.2 (M+1), Rt=1.65 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])SC)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:37][O:38][NH2:39]>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:39][O:38][CH3:37])=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(=NC(=O)OC(C)(C)C)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: CON
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CONC(=NC(=O)OC(C)(C)C)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
To a mixture of the compound (190 mg) obtained in Example 289, triethylamine (0.14 ml), O-methylhydroxylamine hydrochloride (84 mg) and acetonitrile (5 ml), a solution of silver nitrate (90 mg) in acetonitrile (2 ml) was added and stirred at 0° C. for 15 min. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=3:1) to give the 75 mg of titled compound (yield, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH2:18][CH3:19])=[N:6]1.[OH-].[K+:26]>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH2:18][CH3:19])=[N:6]1.[K+:26]
Reactant: CCc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)[O-])ccc12

Procedure:
To a solution of the compound [140](42 mg) in ethanol (1 mL) was added an aqueous solution of 1N-potassium hydroxide (116 μL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (110 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[N:19]2[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.O>C1COCC1.[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[N:19]2[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)Nc2ccc(Br)cc2)CC1
Agent: [Ni]
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: O
Solvent: C1CCOC1
Product: CC1CCN(c2ccc(N)cc2C(=O)Nc2ccc(Br)cc2)CC1

Procedure:
Prepared analogously to Example 4b from N-(4-bromophenyl)-2-(4-methyl-piperidin-1-yl)-5-nitro-benzoic acid amide and Ra-Ni in THF. Yield: (quantitative). MS [M+H]+=388 (Br-isotope pattern); Rt=1.36 min (Method MC-1).
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.C(#N)C.[CH3:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([C:27]#[N:28])=[CH:24]2)=[CH:19][CH:18]=1.[Br:29]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.O>[Br:29][CH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([C:27]#[N:28])=[CH:24]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc2ccc(C#N)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2ccc(CBr)cc2c1
Yield: 82 %

Procedure:
2,2′-azobisisobutyronitrile (982 mg, 6 mmol) and acetonitrile (100 ml) were added to 7-methyl-2-naphthalene carbonitrile (10.0 g, 60 mmol) at room temperature. N-bromosuccinimide (10.6 g, 60 mmol) was added thereto, and the mixture was subjected to heating and refluxing for 2 hours. The resultant mixture was cooled to room temperature. Water (100 ml) and toluene (100 ml) were added to the mixture for extraction. The resultant organic layer was washed twice with water (100 ml). After concentration of a part of the organic layer under reduced pressure, analysis of the residue by reversed-phase chromatography by use of the obtained product from Example 11 as a standard sample revealed that 12.1 g of the title compound was obtained (82% yield).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1.[Li]CCCC.CN([CH:24]=[O:25])C.[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH3:15][C:10]1([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[CH:24]=[O:25])[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2cccc(Br)c2)OCCO1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(c2cccc(C=O)c2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(3-bromo-phenyl)-2-methyl-[1,3]dioxolane (944 mg, 3.88 mmol) in THF (20.0 mL) at −78° C. was added dropwise n-BuLi (1.60 mL of a 2.5M solution in hexane, 4.00 mmol). The reaction mixture was then stirred at −78° C. for 30 min before DMF (0.40 mL, 5.17 mmol) was added dropwise. The reaction mixture was allowed to warm to rt over 1 h. Sat. aq. NH4Cl was added and the mixture was extracted three times with Et2O. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the crude title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.87 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)ccc1Br
Agent: Cl
Product: COC(=O)c1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0° C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92% yield). TLC Rf=0.6 (5% EtOAc-hexanes); HPLC RT=3.48 min, method A; 1H NMR (CDCl3, 400MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz); 7.30 ppm (dd, 1H, J=8.6, 2.5 Hz); 3.94 ppm (s, 3H).