Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.ClCCl.[CH3:12][N:13](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 46 %

Procedure:
Slurry 2,5-dichloropyridine (6 g, 40.5 mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc (dust) (116 mg, 1.8 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (720 mg, 0.98 mmol) in anhydrous DMF (40 mL). Heat the mixture to reflux under a nitrogen atmosphere for 4.5 h. Cool the mixture to room temperature, dilute with EtOAc (300 mL), wash with aqueous 10% sodium chloride (3×75 mL). Collect organic layer, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1 gradient) to obtain the desired intermediate (2.6 g, 46%). GC-MS m/z: 138 (M+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(O)CCC>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: C1COCCN1
Solvent: CCCCO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCOCC3)n3nccc3n2)cc1
Temperature: 100 °C
Yield: 54 %

Procedure:
N-(7-Chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D) (1.0 equivalent) and morpholine (2.0 equivalent) were dissolved in dry n-butanol (0.1 M) under nitrogen. The mixture was heated to 100° C. for 18 h. Next day, lower temperature to room temperature, and product precipitates. The precipitate was collected by filtration and then washed with diethyl ether to give the titled compound (54%) as a pink solid. Melting point (225.0-229° C.). 1H NMR (400 MHz, MeOD) δ ppm 3.31 (s, 6H) 3.70-3.79 (m, 4H) 3.90-3.98 (m, 4H) 6.35 (d, J=2.27 Hz, 1H) 7.40 (s, 1H) 7.66 (d, J=8.59 Hz, 2H) 7.94 (d, J=8.59 Hz, 2H) 8.01 (d, J=2.27 Hz, 1H). ESI-MS: m/z 382.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>C(N(CC)CC)C.[Cu]I>[OH:29][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)CC(c2ccc(C#CCO)cc2)c2ccccc2C)ccn1
Reaction time: 3 h
Yield: 70 %

Procedure:
To 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one ((example 74, step 5), 400 mg) in triethylamine (4.1 mL) tetrakis(triphenylphosphine)palladium (59 mg) and CuI (10 mg) were added. At 80° C. 2-propyn-1-ol (0.12 mL) was added slowly, and the solution was stirred at that temperature for 3 hours. The solution was concentrated in vacuo and redissolved in EtOAc and a saturated solution of NH4Cl. The phases were separated and the inorganic one extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 2:1) to yield the title compound (264 mg, 70%) as a yellow oil, MS (ESI+): m/z=370.1 ([M+H]+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[NH:13][N:14]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].CCN(CC)CC.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>C1(C)C=CC=CC=1>[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH:34][C:2]([NH:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[NH:13][N:14]=2)=[CH:8][CH:9]=1)=[O:3])[CH3:30]
Reactant: CCN(CC)CCN
Reactant: O=C=Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 95 °C
Yield: 57 %

Procedure:
A suspension of of 3-(4-isocyanatophenyl)-1,4-dihydroindeno[1,2-c]pyrazole, 2 (75 mg, 0.274 mmol), Et3N (0.191 mL, 1.37 mmol), N,N-diethylethylenediamine (0.112 mL, 1.37 mmol) in toluene (3 mL) was heated to about 95° C., for about 3 hours. The white solid was filtered off and washed with EtOAc and dried under vacuum to afford 61 mg (57%) of pure product. LC/MS 390 (M+1); LC retention time 2.76 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:23]4[C@@H:19]([O:20]C(C)(C)[O:22]4)[C@H:18]([O:26]C)[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.FC(F)(F)C(O)=O>O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:23]([OH:22])[C@@H:19]([OH:20])[CH:18]([OH:26])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: CO[C@@H]1O[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)[C@H]2OC(C)(C)O[C@@H]12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3OC(O)[C@H](O)[C@@H]3O)c21
Temperature: 80 °C

Procedure:
To a suspension of 4-Amino-5-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide (Example 265b) (15 mg, 0.038 mmol) in water (1 mL) was added trifluoroacetic acid (0.2 mL) and the mixture was heated overnight at 80° C. The reaction mixture was evaporated to dryness to furnish the title compound as a white solid in quantitative yield (mixture of diastereomers ˜10/1). 1H NMR (400 MHz, DMSO-d6): δ 3.71 (m, 4H), 4.12 (m, 3H), 4.35 (m, 1H), 5.02 (s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 8.03 (br s, 1H), 8.31 (br s, 1H), 10.96 (br s, 1H), [11.00 (br s, 0.1H)].
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CN([CH:27]=[O:28])C.[NH4+].[Cl-]>>[CH2:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[CH:27]=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCc1ccsc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CCCCCCCCCCCCc1ccsc1C=O
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of n-Butyllithium (1.6M in hexanes, 8 mL, 12.67 mmol) was added dropwise at −78° C. under N2 to a stirred solution of 2-bromo-3-dodecylthiophene (10) (4 g, 12.07 mmol in 96 mL of ether). During the whole addition, the reaction temperature was kept at −78° C. At this temperature, DMF (1.4 mL, 18.11 mmol) was slowly added and the mixture was allowed to warm to room temperature. The mixture was poured into a 1 M aqueous solution of NH4Cl and extracted with CH2Cl2. The organic layer was washed with water, dried over Na2SO4, and evaporated under reduced pressure. The residue was passed through a short column (silica gel, hexane/ethylacetate, 9:1) to give a light yellow liquid compound 11 in 87% yield. 1H-NMR (DCM-d2, 400 MHz) ppm 0.88 (t, 3H, J=6.8 Hz) ppm 1.27 (m, 18H) ppm 1.67 (td, 2H, J=7.6 Hz, J=15.1 Hz) ppm 2.96 (t, 2H) ppm 7.04 (d, 1H, J=5.0 Hz) ppm 7.66 (d, 1H, J=5.0 Hz) ppm 10.04 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[CH:16][C:15]3=[CH:18][CH:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=4)[N:14]3[N:13]=2)[CH:6]=1)C.O>[OH-].[Na+].C1COCC1>[C:29]([NH:28][S:27]([C:23]1[CH:22]=[C:21]([C:20]2[N:14]3[C:15]([CH:16]=[N:17][C:12]([NH:11][C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:4]([OH:35])=[O:3])=[N:13]3)=[CH:18][CH:19]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:33])=[O:34])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1cccc(Nc2ncc3ccc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)n3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4cccc(C(=O)O)c4)nn23)c1

Procedure:
3-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-benzoic acid ethyl ester (77.0 mg, 0.156 mmol) was taken up in 2 M of Sodium hydroxide in water (2.00 mL, 5.00 mmol) and 2 ml THF, heated for 72 h at 60° C. Concentrated down THF, neutralized aq layer, and extracted with CH2Cl2. Dried, filtered, and concentrated. Took residue up in DMSO and purified by Gilson RP-HPLC. LCMS=465.9 (M+H), HPLC rt=3.199, purity=98%. 1H NMR (400 MHz, CDCl3, δ, ppm): 12.95 (bs, 1H), 9.74 (s, 1H), 9.07 (s, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.72 (dd, J=8.3 Hz, 7.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.47 (dd, J=7.6 Hz, 8.3 Hz, 1H), 7.24 (d, J=4.6 Hz, 1H), 7.04 (d, J=4.9 Hz, 1H), 1.1 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CCOCC>C1COCC1>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][C:7](=[O:12])[NH:6][C:5]2[CH:13]=[CH:14][C:2]([I:1])=[CH:3][C:4]=2[C:10]1=[O:11])[CH3:19]
Reactant: O=C1CCC(=O)c2cc(I)ccc2N1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C=C1CC(=O)Nc2ccc(I)cc2C1=O
Temperature: 70 °C

Procedure:
To a solution of 7-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-a) (1.67 g, 5.54 mmol) in THF (15 mL) was added dimethylformamide dimethylacetal (4.0 mL, 27.7 mmol) and the reaction mixture heated to 70° C. for 1 h. The reaction mixture was cooled to 22° C., treated with Et2O (50 mL), and the resulting precipitate filtered and dried in vacuo to give v-a (1.64 g, 83%) as a brown powder: MS m/z═357 (M+H).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[CH:11][C:12]3[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[C:29](Cl)=[O:30]>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[C:29]([C:11]1[C:12]2[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=2[N:9]2[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=12)=[O:30]
Reactant: O=C(Cl)c1nc2ccccc2s1
Reactant: CC(C(=O)[O-])C1CCn2c1cc1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(C(=O)c1nc3ccccc3s1)c1c(Br)cc(F)cc12

Procedure:
Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 7, Step 8) and 1,3-benzothiazole-2-carbonyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: C(OC(=O)[N:7]([C:20]1[C:21]2[N:22]([N:34]=[CH:35][N:36]=2)[C:23]([C:26]2[O:27][CH:28]=[C:29]([C:31](=[O:33])[NH2:32])[CH:30]=2)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:20]3[C:21]4[N:22]([N:34]=[CH:35][N:36]=4)[C:23]([C:26]4[O:27][CH:28]=[C:29]([C:31]([NH2:32])=[O:33])[CH:30]=4)=[CH:24][N:25]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2cc(C(N)=O)co2)n2ncnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1coc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3ncnn23)c1

Procedure:
A solution of [5-(4-carbamoyl-furan-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (33 mg, 0.065 mmol) in a mixture 1:1 DCM:TFA (2 mL) (2 drops of water) is stirred at room temperature for 2 hours. After addition of sat. Na2CO3, a precipitate is formed, collected by filtration and washed with water, diethyl ether and petroleum ether. After drying under vacuum, the title compound is isolated (20 mg, 76%). Conversion into the mesylate salt using 0.1M methanesulfonic acid in MeOH (0.444 mL) yields the title compound (19 mg, 100%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.36 (3H, s, MsOH), 3.22 (4H, m), 3.82-3.89 (4H, m), 7.13 (2H, d), 7.36 (1H, br s), 7.86 (1H, s), 7.95 (3H, m), 8.17 (1H, s), 8.40 (1H, s), 8.84 (1H, s), 10.17 (1H, s). LCMS: Rt 2.60 min (96.9%), m/z (APCI) 406 (M+H)+.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:21])([CH3:20])[CH2:11][C:10]2=O.CN1CCCN(C)C1=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:21])([CH3:20])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: COc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reaction time: 12 h

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 3.15 mL, 6.29 mmol), 6-bromo-8-chloro-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 9, 400 mg, 1.26 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 2 mL) in THF was reacted then quenched with 10% HCl, and stored at room temperature for 12 h. Purification by flash chromatography (silica gel, 95:5 hexane/ethyl acetate) afforded the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:26])=[C:4]([C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:22]([O:21][C:19]([NH:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([CH3:26])[C:2]([CH:27]=[CH2:28])=[CH:17][CH:16]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)OCc2ccccc2)c1C
Temperature: 90 °C

Procedure:
A mixture of Example 126A (1.4 g, 3.3 mmol), DMF (33 mL) and tributyl(vinyl)tin (1.1 mL, 3.8 mmol) was degassed with argon 30 minutes, treated with Pd(PPh3)4 (577 mg, 0.5 mmol), heated to 90° C. for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel (200 g) with 50% dichloromethane/hexanes to provide the desired product. MS (ESI(+)) m/e 368 (M+H)+; (ESI(−)) m/e 366 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.54 (d, 1H), 7.45 (m, 2H), 7.37 (m, 3H), 7.27 (d, 1H), 6.94 (dd, 1H), 5.64 (dd, 1H), 5.31 (dd, 1H), 5.27 (s, 2H), 2.21 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[C:12]1[CH2:17]Cl.[NH3:20].[I-].[K+]>O1CCCC1.CO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]2[N:11]3[C:15]([CH3:16])=[N:14][N:13]=[C:12]3[CH2:17][NH:20][C:3](=[O:19])[C:4]=2[CH:9]=1
Reactant: N
Reactant: COC(=O)c1cc(Cl)ccc1-n1c(C)nnc1CCl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(=O)NC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A stirred solution of 5-chloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzoic acid methyl ester (VIb)(300 mg., 1 mmole) in tetrahydrofuran (THF) (10 ml.) was cooled, under nitrogen, in an ice bath and treated with 8 ml. of a saturated solution of ammonia in methanol. The mixture was kept in the ice bath for 20 minutes and at ambient temperature for one hour. At this time there was no reaction by thin layer chromatography (TLC). The mixture was therefore treated with potassium iodide (166 mg., 1 mmole) and kept at ambient temperature for 18 hours. It was concentrated in vacuo, and the residue was mixed with water and extracted with chloroform. The extract was washed with brine, dried (Na2SO4) and concentrated. The residue was crystallized from a methanol/ethyl acetate mixture to give 0.169 g., melting point 253.5°-255.5° and 0.026 g., melting point 251°-252.5°. The mixture melting point with that of an authentic sample of the titled compound (VIIa) was 261.5°-264.5°. The first crop was recrystallized from a methanol/ethyl acetate mixture, seeding with an authentic sample, to give 0.110 g., melting point 262°-264°. This was identical to the authentic sample of (VIIa) by ir comparison.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=3)[NH:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Product: COC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1

Procedure:
Following the method of Example 1, N-methyl-4-piperidone (-0.68 g) and methyl 1H-indole-5-carboxylate (0.5 g) gave the title compound as microcrystals (0.18 g), m.p. 202°-204° following recrystallisation from ethyl acetate.
Reaction SMILES: [C:1]([O:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)(=[O:17])C>>[C:1]([O:7][CH:8]1[CH2:13][CH2:12][C:11]([OH:17])([CH3:14])[CH2:10][CH2:9]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)O
Reactant: CC1CCC(OC(=O)C(C)(C)C)CC1
Product: CC1(O)CCC(OC(=O)C(C)(C)C)CC1

Procedure:
FIG. 2 represents chemical structures, reaction schemes and reaction yields for an example of an oxidation of the substrate 4-methylcyclohexyl pivalate in the presence of two different complexes. Experimental details are provided in Examples 3 and 4. Reaction of the substrate with complex 4 in the presence of acetic acid (AcOH) yielded 38% (by GC) of the mono-oxidized product 4-hydroxy-4-methylcyclohexyl pivalate (entry 4). This yield was amplified by using a three-fold reagent addition procedure, in which each addition of the complex included 5 mol % complex 4 and 0.5 equivalent AcOH, and each addition of oxidant included 1.2 equivalents H2O2. The three-fold reagent addition procedure was carried out over a period of 30 minutes, providing diastereomerically pure hydroxylated product 2 in 51% isolated yield (entry 5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.CC1C2C(=CC=CC=2)C([C:50]2[N:51]=[C:52]([NH2:55])[S:53][CH:54]=2)=CC=1.C(N(C(C)C)CC)(C)C>CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10]([NH:55][C:52]2[S:53][CH:54]=[CH:50][N:51]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2csc(N)n2)c2ccccc12
Reactant: CC(C)(C(=O)O)C(c1ccc(F)cc1)c1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccc(F)cc1)c1ccc(N2CCOCC2)cc1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
To a solution of the acid of Preparation 14a (51 mg, 0.142 mmol) in CH3CN (3 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (48.3 mg, 0.213 mmol) and 1-hydroxy-7-benzotriazole (HOBt) (34 mg, 0.213 mmol). After stirring for 5 minutes, to the solution were added 4-(4-methyl-naphthalen-1-yl)-thiazol-2-ylamine (50.4 mg, 0.426 mmol) and diisopropylethyl amine (0.742 ml, 0.426 mmol). The reaction was heated at 75° C. for 12 hours. The reaction mixture was filtered, and purified by preparative HPLC to give the title compound of Example 222 as a white solid (36 mg, 58% yield). LC/MS (m/z) 440.17 [(M+H)+]; HPLC Rt: 3.12 min. 1H NMR (400 MHz, CDCl3): δ 7.34 (1H, m), 7.18-7.26 (5H, m), 6.79-6.93 (4H, m), 4.42 (1H, s), 3.78 (4H, m), 3.06 (4H, m), 1.34 (6H, s). LC/MS (m/z) 440.17 [(M+H)+]; HPLC Rt: 3.120 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[C:13]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[O:9])=[CH:6][CH:5]=1.[CH3:30][O:31][CH2:32][CH2:33]Cl>CS(C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:33][CH2:32][O:31][CH3:30])[C:15](=[O:20])[CH:14]=[C:13]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[O:9])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Sodium hydride (601 g) was added portionwise under N2 flow to a solution of interm. (9-d) (15 g) in dimethyl sulfoxide (200 ml). The mixture was stirred at room temperature for 30 minutes. 2-Chloroethyl methyl ether (25.2 ml) was added. The mixture was stirred at 50° C. for 72 hours, poured out on ice and extracted with ethyl acetate. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate 70/30). The pure fractions were collected and the solvent was evaporated, yielding 6.2 g (36%) of 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-(2-methoxyethyl)-2(1H)-quinolinone (interm. 9-e).
Reaction SMILES: [C:1](N1C=CN=C1)(=[O:3])[CH3:2].[CH3:9][C:10]([NH:13][CH2:14][CH:15]([OH:26])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[CH:25])([CH3:12])[CH3:11]>C1COCC1>[C:1]([O:26][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[CH:25])[CH2:14][NH:13][C:10]([CH3:9])([CH3:11])[CH3:12])(=[O:3])[CH3:2]
Reactant: C#Cc1ccccc1OCC(O)CNC(C)(C)C
Reactant: CC(=O)n1ccnc1
Solvent: C1CCOC1
Product: C#Cc1ccccc1OCC(CNC(C)(C)C)OC(C)=O
Reaction time: 1 h

Procedure:
A 4.8 g (42.8 mmole) sample of 1-acetylimidazole was added to a solution of 5.14 g (20.8 mmole) of 1-[(1,1-dimethylethyl)amino]-3-(2-ethynylphenoxy)-2-propanol in 28 ml THF. The mixture was stirred under N2 for one hour. The mixture was partitioned between water and ether. The ether layer was washed with brine, dried (K2CO3) and the solvent evaporated in vacuo to give the title compound as an oil, 6.14 g.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CN1CCCC1=O.C(OCC)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(CBr)OCC
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCOC(COc1ccc(C=O)cc1)OCC
Yield: 96.6 %

Procedure:
Bromoacetaldehyde-diethyl-acetal (98.5 g, 0.5 m) and p-hydroxybenzaldehyde (76.4 g, 0.63 m) were dissolved in N-methylpyrrolidone (250 cm3) and heated at 120° for 12 hours. The reaction mixture was cooled, diluted with diethyl ether and the ether layer was extracted four times with 5% sodium hydroxide solution to remove excess of p-hydroxybenzaldehyde. The ether was removed and the product distilled under reduced pressure to give 115 g (97%) of p-formylphenoxy-acetaldehyde-diethyl-acetal, b. 139°-140°/1.5 mbs. Acetylbenzene-sulphonic acid (sodium salt, 40 g, 0.18 m) was dispersed in a mixture of methanol (400 cm3) and 10% aqueous sodium hydroxide (150 cm3).
Reaction SMILES: [NH2:1][CH:2]([C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1)[CH3:3].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[C:9]1([C:4]2([CH:2]([NH:1][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:3])[O:5][CH2:6][CH2:7][O:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(N)C1(c2ccccc2)OCCO1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC(C)C1(c2ccccc2)OCCO1

Procedure:
A solution of 2-(1-aminoethyl)-2-phenyldioxolane (20 mmoles), triethylamine (24 mmoles), and ethyl chloroformate (22 (mmoles) in 100 ml of dichloromethane is stirred at 0°C for 2 hours, washed with water, dried, and evaporated to give the title compound.