Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:40]=[CH:39][C:10]([C:11]([C:13]3[CH:32]=[CH:31][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[C:21]([O:29][CH3:30])[CH:20]=4)=[C:15]([CH2:33][CH2:34][C:35]([O:37]C)=[O:36])[CH:14]=3)=[O:12])=[C:9]([OH:41])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.C(OCC)(=O)C>CO.O1CCCC1.[OH-].[Na+]>[C:35]([CH2:34][CH2:33][C:15]1[CH:14]=[C:13]([C:11](=[O:12])[C:10]2[CH:39]=[CH:40][C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[OH:41])[CH:32]=[CH:31][C:16]=1[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[C:21]([O:29][CH3:30])[CH:20]=1)([OH:37])=[O:36]
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc(C(=O)OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2ccc(C(=O)c3ccc(OC4CCCC4)cc3O)cc2CCC(=O)O)ccc1C(=O)O
Reaction time: 1 h
Yield: 45.1 %

Procedure:
0.98 g of methyl 4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-oxopropyl)phenoxy]methyl}-2-methoxybenzoate was dissolved in a mixed solvent of 10 mL of methanol and 10 mL of tetrahydrofuran, to which 2 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and then this mixture was stirred for one hour at the same temperature. The reaction mixture to which water was added was adjusted to pH 2 with 6M hydrochloric acid, followed by the addition of ethyl acetate thereto, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out under reduced pressure. The resultant residue was recrystallized from ethanol to yield 0.42 g of 4-({2-(2-carboxyethyl)-4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl)-2-methoxybenzoic acid as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: NC(=O)c1ccc(Cl)c(Br)c1
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(Br)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 3-bromo-4-chlorobenzamide (1.6 g, 6.8 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (1.36 mL, 13.6 mmol) at room temperature. The mixture was then heated to 60° C. for 8 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When bubbling ceased, 1N HCl was added until pH was ˜2. The mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous phase was washed 3× with EtoAC. The aqueous was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were washed with brine (1×) and dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound as a clear oil. LC-MS m/z 219.6 (M+H)+, 1.41 min (ret time).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9].[CH3:24][O:25][P:26]([O:29]C)[O:27][CH3:28]>>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][P:26](=[O:29])([O:27][CH3:28])[O:25][CH3:24])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:13][CH:14]3[CH2:20][CH:18]([CH2:17][CH:16]([CH2:15]3)[CH2:21]1)[CH2:19]2)=[O:9]
Reactant: COP(OC)OC
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Product: COP(=O)(Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)OC

Procedure:
5-Bromomethyl-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (5.70 g, Example 8b) in 100 ml of trimethylphosphite was heated at reflux for 15 h. The solvent was removed by azeotropic distillation with toluene under high vacuum to afford the subtitle compound as a yellow solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[CH:24]([C:26]1[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][CH:27]=1)=O>CO>[N:19]1([C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([C:7]3[N:8]=[C:9]4[NH:10][C:24]([C:26]5[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][CH:27]=5)=[N:3][C:4]4=[CH:5][CH:6]=3)[CH2:12]2)=[O:18])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: COC(=O)c1cccc(C=O)n1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)n1

Procedure:
(R)-Methyl 6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)picolinate (150 mg) was prepared by a method analogous to the one used for Example 112, but using (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Intermediate 1, Step 3), methyl 6-formylpicolinate, and methanol as the solvent. MS (ES+) (M+H) 434.67; LCMS retention time 5.39 min (Method H).
Reaction SMILES: C(OC(=O)C)C.Cl.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:55])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[C:32]([NH:34][C:35]2[CH:44]=[CH:43][C:38]3[O:39][CH2:40][CH2:41][O:42][C:37]=3[CH:36]=2)=[O:33])=[CH:26][CH:25]=1)=O)(C)(C)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CO>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:55])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[C:32]([NH:34][C:35]2[CH:44]=[CH:43][C:38]3[O:39][CH2:40][CH2:41][O:42][C:37]=3[CH:36]=2)=[O:33])=[CH:26][CH:25]=1
Reactant: CN1CCN(CCCN(Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)C(=O)Nc2ccc3c(c2)OCCO3)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(CCCN(Cc2ccc(C(=O)Nc3ccccc3N)cc2)C(=O)Nc2ccc3c(c2)OCCO3)CC1
Yield: 82 %

Procedure:
4.0 M hydrogen chloride ethyl acetate solution (10 mL) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-4-[3-(2,3-dihydrobenz o[1,4]dioxin-6-yl)-1-[3-(4-methylpiperazine-1-yl)propyl]ureidomethyl]benzamide (Reference Compound No. 13-1, 450 mg, 0.68 mmol) in a mixed solvent (ethyl acetate (10 mL) and methanol (10 mL)), and then the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate solution (150 mL) was added thereto, the whole was extracted with chloroform (150 mL), and then the organic layer was washed with brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH-modified silica gel, chloroform-methanol) to give 310 mg of the title compound as a colorless amorphous product. (Yield 82%)
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Cl.[NH:35]1CCC1>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:35]
Reactant: C1CNC1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 29.5 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.300 g, 0.770 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (20 mL) under Ar. K2CO3 (0.320 g, 2.320 mmol, 3 eq) was added followed by the addition of azetidine hydrochloride (0.217 g, 2.320 mmol, 3 eq). The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.030 g (11%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 349 (M+1); Anal. Calcd for C22H24N2O2.1HCl.0.75H2O: C, 73.00; H, 7.10; N, 7.74; Found: C, 73.06; H, 6.95; N, 7.51.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][C@@H:16]([OH:24])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:5])[CH3:2]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][C@@H:16]([OH:24])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NC[C@@H](O)CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c[nH]c1CCNC[C@@H](O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
(R)-2-[(2-hydroxy-3-morpholin-4-yl-propylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 5c (2.332 g, 6.6 mmol) was dissolved in 23 mL of anhydrous tetrahydrofuran under an argon atmosphere, and borane-tertrahydrofuran complex in tetrahydrofuran (23.12 mL, 1 mol/L, 23.12 mmol) was then added dropwise to the solution in an ice-water bath. Upon completion of the addition, the ice-water bath was removed. The reaction system was allowed to warm up to room temperature and refluxed at 95° C. in an oil bath for 1 hour. The reaction was completed until TLC showed the disappearance of starting materials. The solvent was evaporated under reduced pressure, and 5 mL of hydrochloric acid (2N) was then added to the residue. The mixture was stirred for 0.5 hour, and 5 mL of iced water was then added to the mixture. The mixture was adjusted to pH about 10 with 10N sodium hydroxide solution. The mixture was extracted with ethyl acetate (100 mL×2). The combined organic extracts were washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to give the title compound (R)-2-[2-(2-hydroxy-3-morpholin-4-yl-propylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 5d (2.1 g, yield 93.75%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13].CCN(CC)CC.[Cl:21][C:22](OC(Cl)(Cl)Cl)=[O:23]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][O:13][C:22]([Cl:21])=[O:23]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(Br)c1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
A solution of 2-(2-bromo-6-nitrophenyl)ethanol (500 mg, 2.03 mmol) and Et3N (206 mg, 2.03 mmol, dist. over KOH) in THF (5 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (442 mg, 2.23 mmol) in THF (5 ml, see above) for 10 min. It was stirred for 5 min while being cooled in an ice bath and for 1 h 45 min at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF and removing the solvent and the excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2-bromo-6-nitrophenyl)ethoxycarbonyl chloride (625 mg, 99.8%) as a light brown oil.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46]Br)=[CH:40][CH:39]=1>CN(C=O)C>[CH3:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:24])[CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (3.20 g, 9.21 mmol) in DMF (30 mL) at 0° C. was added NaHMDS (1M in THF, 11.5 mL, 11.5 mmol). After 1 h, 4-(3-bromo-propyl)-benzoic acid methyl ester (2.84 g, 11.0 mmol) was added and the reaction mixture was stirred at 70° C. for 18 h. The DMF was removed in vacuo and the residue was dissolved in EtOAc. The organic solution was washed with water, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography (30% EtOAc in hexanes) to yield 3.39 g of 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester. 1H NMR (CDCl3) (selected peaks) δ7.92 (m, 2H), 7.25-7.09 (m, 7H), 3.86 (s, 3H), 3.80 (m, 1H), 3.61 (m, 1H), 3.46 (m, 1H), 2.90 (m, 1H), 2.78-2.57 (m, 4H), 2.38-2.18 (m, 2H), 0.83 (s, 9H); MS 524.1 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[N:12][C:11]=1[CH3:18].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([CH:25]=[CH:26][CH:27]=[O:28])=[CH:23][CH:22]=1>O1CCCC1>[OH:28][CH:27]([CH:26]=[CH:25][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:30][CH:29]=1)[CH2:18][C:11]1[C:10]([CH3:9])=[N:15][C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=1
Reactant: Cc1nc(C)c(C)nc1C
Reactant: COc1ccc(C=CC=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C=CC(O)Cc2nc(C)c(C)nc2C)cc1
Temperature: 25 °C

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of tetramethylpyrazine (13.6 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of p-methoxycinnamaldehyde (17.8 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedures of Example I to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:14](I)=[C:13]([I:16])[N:12]=[C:11]1[CH2:17][CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].CC[Mg+].[Br-].O.CCOCC>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:16])[N:12]=[C:11]1[CH2:17][CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Agent: CC[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc(I)cn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of [2-(4,5-diiodo-2-propyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (8.690 g; 17.204 mmol) in anhydrous THF (100 ml), under nitrogen, was cooled to −40° C., and a solution of 1M EtMgBr in THF (20.5 ml; 20.5 mmol; 1.2 eq.) was then added dropwise over 15 min. After addition, the resulting solution was stirred between −40° C. and −30° C. for 10 min. (conversion=55% according to LC-MS), and additional 1M EtMgBr in THF (13.9 ml; 13.9 mmol; 0.8 eq.) was added in order to complete the reaction. The reaction mixture was then treated with water (5 ml) at −40° C., and was allowed to warm-up to rt. Ether (200 ml) was added, and the resulting solution was washed with brine (2×200 ml). The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=20/1) to give the pure product [2-(4-iodo-2-propyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow oil (6.110 g; 94%). LC-MS: tR=0.74 min.; [M+H]+=380.00 g/mol.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: C1=COCCC1
Reactant: OCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.58 ml of 3-bromo-1-propanol was dissolved in 6 ml of dry dichloromethane, and 1.22 ml of dihydropyrane and 10 mg of dry p-toluenesulfonic acid were added thereto. The mixture was stirred at room temperature overnight. The reaction solution was separated with 30 ml of chloroform and 15 ml of a 4% sodium hydrogencarbonate aqueous solution. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated by silica gel column chromatography (chloroform). Then, the fraction containing the product was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1). The combined fraction containing the product was subjected to the removal of the solvent under reduced pressure to obtain 1.44 g of 3-bromo-1-(2-tetrahydropyranyloxy)propane as colorless oily substance.
Reaction SMILES: Br[CH:2]([CH2:5]Br)[CH2:3][OH:4].[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10].Cl>[I-].[K+].C(O)(C)C>[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH:10][CH:2]([CH2:5][NH:10][C:9]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:8]=1[CH3:7])[CH2:3][OH:4]
Reactant: Cc1cccc(C)c1N
Reactant: OCC(Br)CBr
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cccc(C)c1NCC(CO)Nc1c(C)cccc1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
A mixture of 109 g (0.5 moles) of 2,3-dibromo-propan-1-ol, 248 ml (242.4 g, 2.0 moles) of 2,6-dimethylaniline and 1.0 g (6 mmoles) of potassium iodide is stirred at 140° to 145° C. for 3 hours under nitrogen atmosphere. The mixture is allowed to cool to about 80° C., and 100 ml of isopropanol, followed by 500 ml of 20% aqueous hydrochloric acid, are added. The mixture is allowed to stand overnight, thereafter the separated precipitate is filtered off, washed with water and dried. The resulting solid, weighing 170 g, is dissolved in 1500 ml of methanol, the pH of the solution is adjusted to 10 with 10 n aqueous sodium hydroxide solution, and the mixture is diluted with 1500 ml of water. The separated precipitate is filtered off, washed with water and dried. 99 g (66.4%) of crude 2,3-bis(2',6'-dimethylphenylamino)-1-propanol are obtained. The product melts at 92°-94° C. after recrystallization from methanol.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1ccncc1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 19) was reacted with pyridin-4-yl-boronic acid to give the title compound as colorless oil. MS: 500.2 (MH+).
Reaction SMILES: [F:1][CH:2]([F:32])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:31]=[CH:30][C:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][C:23]=4[CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[F:32][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:31]=[CH:30][C:24]4[CH2:25][CH2:26][N:27]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:28][CH2:29][C:23]=4[CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C(=O)CCl
Reactant: FC(F)COc1ccccc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5ccccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-Difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.100 g, 0.230 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.035 mL, 0.344 mmol) in a manner analogous to Example 313 to give product (0.045 g, 38%). MP=213-215° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.49 (s, 1H), 8.77 (d, 1H), 7.65 (m, 2H), 7.40 (m, 2H), 7.35 (s, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.22 (br m, 1H), 4.35 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 2.75 (m, 7H), 2.55 (m, 4H). MS=521 (MH)+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH2:4].[Cu][C:12]#[N:13].N>CN1CCCC1=O>[C:12]([C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH2:4])#[N:13]
Reactant: Cc1cc(Br)c(N)cc1Cl
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 2-bromo-5-chloro-4-methylaniline (13.0 g 58.96 mmol) in N-methylpyrrolidinone (100 ml) was added copper(I) cyanide (10.56 g, 118 mmol). The reaction mixture was placed in an oil bath preheated to 163° C. and stirred at this temperature for 2 h. The reaction mixture was allowed to cool to room temperature and then poured in ice-water (300 ml) and aqueous ammonia (90 ml). The brown precipitate was collected by filtration, washed with water (150 ml), dissolved in dichloromethane and the insoluble material was removed by filtration. The filtrate was washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo. Purification, on gradient elution with dichloromethane in petroleum ether 60-80° C. (65 to 95%), afforded a white solid (6.52 g), mp 180° C.; 1H-NMR (DMSO-d6) 2.14 (s, 3H, 4-CH3), 6.11 (s, 2H, NH2), 6.86 (s, 1H, 6-H), 7.39 (s, 1H, 3-H); MS (FAB, m/z) 166,168 [(M+H)+; 90%, 40% respectively; Cl isotopic pattern]; FAB-HRMS: measured 166.0307; calculated for C8H8ClN2 (M+H)+ 166.0298.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:19][CH:20]=O)([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[B-](F)(F)F.C([N+]1C2C=CC=CC=2OC=1Cl)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N+:19]#[C-:20])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CCCCC(Cn1cncn1)(NC=O)c1ccc(Cl)cc1
Agent: CC[n+]1c(Cl)oc2ccccc21
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [C-]#[N+]C(CCCC)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 0.40 g (1.3 mmols) of N-[2-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-2-hexyl]formamide in 5mL of methylene chloride under nitrogen was added 0.45 mL (3.26 mmols) of triethylamine. To this mixture was added a slurry of 0.439 g (1.63 mmols) of 3-ethyl-2-chlorobenzoxazolium tetrafluoroborate. which was weighed out under a nitrogen atmosphere, in 5 mL of methylene chloride. The reaction mixture was then allowed to stir at room temperature for 12 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed once with 10% hydrochloric acid, brine, and dried over magnesium sutfate. Removal of solvents gave a crude oil which was purified by column chromatography (Merck 60 silica gel, ethyl acetate/hexane) to give 0.20 g (52%) of a clear, colorless oil. 1H-NMR 200 MHz (CDCl3, Me4Si) 0.8 (t, J=5 Hz, CH2 -CH3), 1.0-1.6 (m, 4H, 1.90-2.2 (m, 2H), 4.55 (ABq, J=16.8 Hz, JAB =15 Hz, CH2 -N), 7.2-7.5 (q, 4H, aromatic H), 7.9 (s CH=N), 8.0 ppm (s, CH=N).