Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([Br:12])[N:6]2[N:5]=1.F[B-](F)(F)F.[O:19]=[N+:20]=[O:21]>C(#N)C>[CH3:1][O:2][CH2:3][C:4]1[C:13]([N+:20]([O-:21])=[O:19])=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([Br:12])[N:6]2[N:5]=1
Reactant: COCc1cc2cccc(Br)n2n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 46 %

Procedure:
To a solution of (7-bromopyrazolo[1,5-a]pyridin-2-yl)methyl methyl ether (1.0 g) dissolved in acetonitrile (20 mL) was added nitronium tetrafluoroborate (606 mg) while stirring on ice. The obtained reaction mixture was added to ice water, extracted with ethyl acetate and then washed with water and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (546 mg) was obtained as light yellow crystals from the n-hexane:ethyl acetate (5:1) fraction.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1ccc(-c2ccccn2)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(-c3ccccn3)s1)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
A mixture of 2.3 g of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 3.6 g (15 mmol) of 2-(5-bromo-2-thienyl)pyridine, 0.39 g of triphenylphosphine, 95 mg of cuprous iodide, 3 ml of triethylamine and 100 ml of acetnitrile was degassed with argon for 10 minutes. Palladium acetate, 110 mg, was then added and the mixture was stirred at room temperature for 18 hrs. After evaporation under reduced pressure, the residue was partitioned between methylene chloride and water. The organic layer was dried and evaporated and the residue was chromatographed over 140 g of silica gel using 5% of ethyl acetate in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ether/hexane to yield 2 g of colorless crystals with m.p 159°-162°. The analytical sample was recrystallized from ethanol and had m.p. 160°-162°.
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[C:8]12([CH2:18][NH:19][C:20](=[O:30])[C:21]3[C:26]([Br:27])=[CH:25][N:24]=[C:23]([O:28]C)[CH:22]=3)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>C(#N)C.O>[C:8]12([CH2:18][NH:19][C:20](=[O:30])[C:21]3[C:26]([Br:27])=[CH:25][N:24]=[C:23]([OH:28])[CH:22]=3)[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2
Reactant: COc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Br)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ncc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Sodium iodide (0.48 g) was added to a solution of trimethylsilylchloride (0.41 ml) in acetonitrile (30 ml) and the mixture was stirred for 1 hour. N-(1-Adamantylmethyl)-5-bromo-2-methoxyisonicotinamide (0.94 g) (Example 35(i)) was then added and the reaction mixture was heated at 60° C. under nitrogen for 3 hours. The reaction mixture was diluted with water (150 ml) and the resultant solid was collected by filtration and dried by means of ethanol/toluene azeotrope. The solid was triturated with diethyl ether and collected by filtration to afford the sub-titled compound (0.70 g).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27]([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)=[O:28])[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCOCc1cccc(C(=O)O)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCOCc1cccc(C(=O)n2n[n+]([O-])c3ccccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
To a suspension of 1-Hydroxybenzotriazole (0.283 g) and 6-octyloxymethylpicolinic acid (0.505 g) in dichloromethane (15 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.473 g), and stirred for 3 hours at ambient temperature. The reaction mixture was poured into water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-(6-Octyloxymethylpicolinoyl)benzotriazole 3-oxide (737 mg).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][CH:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CN(C)C1CCNC1
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N(C)C)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.26 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 481 [M+H]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]Br.[N+]([O-])(O)=O>S(=O)(=O)(O)O.C(Cl)Cl>[Br:14][C:7]1[CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[CH:4]=[C:3]([N+:11]([O-:13])=[O:12])[C:2]=1[F:1]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(F)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 30 %

Procedure:
To 1-fluoro-2,4-dinitrobenzene (13.0 g, 69.85 mmol, 1 equiv) dissolved in sulfuric acid (190 mL) at room temperature was added bromine (4.30 mL, 83.82 mmol, 1.2 equiv) dropwise followed by the slow dropwise addition of nitric acid (70%, d=1.500; 3.25 mL, 76.84 mmol, 1.1 equiv). The reaction vessel was fitted with a refluxing condenser, and the reaction mixture was heated at 80° C. for 10 hours. LCMS indicated a reactant:product ratio of 1:1. After allowing to cool to room temperature, the mixture was poured into ice and diluted with DCM. The aqueous and organic layers were partitioned, and the aqueous extracted with DCM (2×300 mL). The combined organic extracts were washed with saturated Na2S2O3 (2×200 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified using a pad of silica gel and eluted with EtOAc/hexanes (25-35% EtOAc in increments of 5% EtOAc) to give the product 1-bromo-2-fluoro-3,5-dinitrobenzene (5.55 g, 30%) as a light-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[CH3:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[NH:49][CH2:50][CH2:51][CH2:52][N:53]=2)=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:40]([CH3:39])[CH2:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]4[NH:53][CH2:52][CH2:51][CH2:50][N:49]=4)=[CH:46][CH:47]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(C2=NCCCN2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCCCN4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), N-methyl-1-[4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]methanamine dihydrochloride (42 mg, 0.15 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DCE (2 mL).
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][C:47]4[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[C:50]1([CH3:53])[CH:51]=[CH:52][C:47]([CH2:46][CH2:45][CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:54]=[CH:55][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:56])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])=[CH:48][CH:49]=1
Reactant: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 43.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-[3-(4-methylphenyl)propyl]-1-piperidine-carboxamide (0.185 g, 0.23 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.058 g, 0.1 mmol)
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]\[C:4]([OH:6])=O.CCO[C:12]([CH3:14])=[O:13]>>[OH:13][C:12]1[CH:14]=[C:1]2[C:3](=[CH:2][CH:1]=1)[C:4](=[O:6])[CH2:4][CH2:3][CH2:2]2
Reactant: CCOC(C)=O
Reactant: O=C(O)/C=C\C(=O)O
Product: O=C1CCCc2cc(O)ccc21

Procedure:
6-[(2-Pyrimidinyl)oxy]-tetralone (3.2 mmol), N-cyclohexylpiperazine (3.2 mmol) and Ti(O-2-Pr)4 (3.2 mmol) were dissolved in CH2Cl2 (10 mL). The solution was stirred at room temperature for 20 hours and then quenched with NaCNBH3 (6.4 mmol in 5 mL EtOH). Water (20 mL) was added, the resulting mixture was filtered through a pad of `Celite`, and the residue was rinsed with CH2Cl2 (10 mL). The organic layer was dried with Na2SO4 and evaporated to yield the crude product as an oil. Purification by column chromatography on TLC-grade silica gel and 100:3:1 CH2Cl2 :EtOH:NH4OH as eluant gave the pure product, 4-cyclohexyl-1-piperazinyl-[6-[(2-pyrimidinyl)oxy]]-1,2,3,4-tetrahydro-naphthalene. This was converted to the dimaleate salt, m.p. 179-181.5° C., by dissolving in EtOAc and heating with 2 equivalents of maleic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:40]1([CH:43]=O)[CH2:42][CH2:41]1>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][N:35]4[CH2:43][CH:40]4[CH2:42][CH2:41]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=CC1CC1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4CC4CC4)ncn3)cccc2s1

Procedure:
N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)piperidine-2-carboxamide from step (a) above (0.40 g, 0.72 mmol) was reacted with cyclopropanecarboxaldehyde (0.16 mL, 2.2 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as an off-white solid. MS (ESI, pos. ion.) m/z: 611 (M+1). Mp: 212.3-213.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:21][C:22](=O)N(C)C)=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:35]=[CH:34][C:31](CBr)=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:21][CH2:22][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(=O)Sc1c(C#N)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Fc1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(C#N)c(SCc3ccc(F)cc3)c2CC1
Yield: 86.7 %

Procedure:
Use a method similar to the General Procedure 7, using 3-tert-butoxycarbonyl-7-cyano-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (123 mg, 0.33 mmol) and 4-fluorobenzyl bromide (204 mg, 1.64 mmol), to give 3-tert-butoxycarbonyl-7-cyano-6-(4-fluoro-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (118 mg, 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8]C(=O)C(F)(F)F)[CH:7]=1.[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH2:25][C:26]2[CH:27]=[C:28]([O:42][CH2:43][CH3:44])[C:29](I)=[C:30]([O:32][S:33]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:31]=2)=[CH:20][N:19]=1>>[NH2:8][C:6]1[CH:7]=[C:2]([C:29]2[C:28]([O:42][CH2:43][CH3:44])=[CH:27][C:26]([CH2:25][C:21]3[C:22]([NH2:24])=[N:23][C:18]([NH2:17])=[N:19][CH:20]=3)=[CH:31][C:30]=2[O:32][S:33]([CH2:36][C:37]([CH3:38])([CH3:40])[CH3:39])(=[O:34])=[O:35])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)(C)C)c1I
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)(C)C)c1-c1ccc(OC)c(N)c1
Yield: 27 %

Procedure:
Starting from 197 mg (0.66 mmol) N-(5-bromo-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide and 173 mg (0.33 mmol) 2,2-dimethyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 46 mg of the title compound are obtained as a brownish solid after two chromatography operations.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I:26][CH2:27][CH2:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+].CCOCC>CS(C)=O>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:17])([CH3:18])[C:9](=[O:16])[CH:10]([CH2:30][CH2:29][CH2:28][CH2:27][I:26])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ICCCCI
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C(CCCCI)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (0.5 g), 1,4-diiodobutane(0.23 ml) and potassium carbonate(1.0 g) was stirred in dimethylsulphoxide at 20° C. for 12 hours. The mixture was diluted (ether), washed (brine), dried (MgSO4), evaporated and the residue purified by column chromatography (ethyl acetate/hexane 1:3) to give ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-(4'-iodobutyl)-4-methyl-3-oxo-pentanoate (0.3 g), NMR 1.24(3H, t), 1.3-1.4(2H, m), 1.43((3H, s), 1.48(3H, s), 1.7-2.0(7H, m), 3.12(2H, t), 3.8-3.9(1H, m), 4.1-4.2(2H, m), 5.28(2H, d), 7.2-7.4(5H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](N)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:20]>>[Br:20][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][N:9]=1
Reactant: BrC(Br)Br
Reactant: Nc1n[nH]c2ncc(F)cc12
Agent: CC(C)(C)ON=O
Product: Fc1cnc2[nH]nc(Br)c2c1
Temperature: 61 °C

Procedure:
To a mixture of 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine, 132a, (0.88 g, 5.79 mmol) in bromoform (8.8 mL) was added tert-butyl nitrite (1.38 mL, 11.57 mmol). This mixture was heated to 61° C. for 1 h and then heated to 90° C. for an additional hour. The mixture was cooled to room temperature and bromoform was removed under reduced pressure. The resulting crude residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to afford 970 mg of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 14.22 (s, 1H), 8.67 (dd, J=2.7, 1.9 Hz, 1H), 8.07 (dd, J=8.2, 2.7 Hz, 1H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.42 minutes (M+H) 216.11.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:11])=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C(=O)N1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
A solution of 2-(4-bromophenyl)propanoic acid (215 mg, 0.94 mmol) in dichloromethane (4 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (152 g, 0.94 mmol). This mixture was allowed to stir at room temperature for 15 minutes. Pyrrolidine (67 mg, 0.94 mmol) was then added and the stirring continued for 1 hour at room temperature. Most of the solvent was removed under reduced pressure and the residue added to a 5 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (189 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:31][C:32]([F:42])([F:41])[C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]2[N:8]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:41])[F:42])=[CH:40][CH:39]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Temperature: 0 °C

Procedure:
4,6-dichloro-3H-imidazo[4,5-c]pyridine (500 mg, 2.6 mmol), PPh3 (762 mg, 2.91 mmol) and THF (20 mL) were combined and stirred under a nitrogen atmosphere. A solution of 4-trifluoromethyl benzyl alcohol (513 mg, 2.91 mmol) in THF (5 mL) was added at rt. The reaction mixture was cooled to 0° C., and diisopropyl azodicarboxylate (587 mg, 2.91 mmol) was added dropwise. The reaction was warmed to rt and stirred overnight under N2. The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was dissolved in EtOAc (20 ml), p-toluenesulfonic acid (500 mg, 2.91 mmol) was added at rt, and the mixture was stirred for 3 h. The precipitate which formed was collected by filtration and rinsed with EtOAc. The collected precipitate was slurried in EtOAc (50 mL) and was stirred vigorously with aqueous sat'd NaHCO3 (5 mL) for 30 min. The organic layer was separated, and the aqueous layer was extracted several times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatograhy with 20% to 100% EtOAc/hexanes to obtain the desired isomer, 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. 1H NMR (400 MHz, CDCl3): δ8.85 (s, 1H); 7.96 (s, 1H); 7.71 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 5.89 (s, 2H). MS APCI calc'd. for C14H8Cl2F3N3 [M+H]+ 346. found 346.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
10.8 g (26.2 mmol) of the compound of Example 26A are provided in 236 ml of 1,4-dioxane, 236 ml (472 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 2 h. The mixture is concentrated and a 2N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 9.90 g (99% of theory) of the title compound are obtained.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:58])[CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:57])[C@H:22]([NH:36][C:37]([N:39]3[CH2:44][CH2:43][CH:42]([N:45]4[CH2:51][CH2:50][C:49]5[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=5[NH:47][C:46]4=[O:56])[CH2:41][CH2:40]3)=[O:38])[CH2:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:27]([NH2:34])=[C:26]([Cl:35])[CH:25]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C.Cl>O.C1COCC1>[NH2:34][C:27]1[C:28]([C:30]([F:32])([F:31])[F:33])=[CH:29][C:24]([CH2:23][C@@H:22]([NH:36][C:37]([N:39]2[CH2:40][CH2:41][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:43][CH2:44]2)=[O:38])[C:21]([N:18]2[CH2:17][CH2:16][CH:15]([CH:12]3[CH2:13][CH2:14][N:9]([CH2:8][C:7]([OH:58])=[O:6])[CH2:10][CH2:11]3)[CH2:20][CH2:19]2)=[O:57])=[CH:25][C:26]=1[Cl:35]
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)NC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20.1 mg (0.47 mmol) lithium hydroxide hydrate in 10 mL water was added to a solution of 250 mg (0.32 mmol) ethyl[1′-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-4,4′-bipiperidinyl-1-yl]-acetate (Example 7.5) in 5 mL THF and the reaction mixture was stirred for 2 h at RT. 0.5 mL 1 M HCl were added, the substance precipitated was filtered off and dried at 50° C. The crude product was purified by HPLC.
Reaction SMILES: C(OC1C(=O)C=COC=1[CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)C1C=CC=CC=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C(O)C>[CH2:16]([O:32][C:31]1[C:18](=[O:17])[CH:23]=[CH:22][N:34]([CH2:21][CH2:20][OH:19])[C:33]=1[CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCO
Reactant: O=c1ccoc(C(OC2CCCCO2)c2ccccc2F)c1OCc1ccccc1
Solvent: CCO
Product: O=c1ccn(CCO)c(C(OC2CCCCO2)c2ccccc2F)c1OCc1ccccc1

Procedure:
3-Benzyoxy-1-(2-hydroxy-ethyl)-2-[-2-fluorophenyl)-(tetrahydro-pyran-2-yloxo)-methyl]-1H-pyridin-4oone: 5.66 g of 3-benzyloxy-2-[(2-fluorophenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-pyran-4-one are boiled under reflux for 24 hours in 50 ml of ethanol and 10 ml of ethanolamine. Working-up analogously to Example 1c yields 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[(2-fluorophenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-1H-pyridin-4-one in the form of a semi-crystalline yellow mass. Rf value: 0.2 (silica gel 60, ethyl acetate/ethanol 9/1).