Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]CC)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:35]([Zn+])[CH:36]([CH3:38])[CH3:37]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH2:35][CH:36]([CH3:38])[CH3:37])[N:7]=3)=[CH:33][CH:32]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([OH:28])=[O:27]
Reactant: CC(C)C[Zn+]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)Cc1cccc(NC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (Example 52, Step A, 0.021 g, 0.039 mmol) in THF (0.5 ml) was added 0.5 isobutylzinc bromide in THF (0.12 ml, 0.059 mmol) followed by bis(tri-t-butylphosphine)palladium (0) (0.0010 g, 0.0020 mmol) and the reaction was stirred at ambient temperature for 1 hour. The reaction was loaded onto silica gel and the product eluted using 3:1 hexanes/ethyl acetate. The resulting oil was dissolved in THF/MeOH/1N NaOH (0.5 ml/0.5 ml/0.25 ml) and stirred at ambient temperature for 3 hours. The reaction was diluted with DCM (35 ml) and washed with water with made acidic (pH=5) with 1N HCl. The organic layer was washed with brine (10 ml), dried over magnesium sulfate and concentrated to give the title compound (0.013 g, 0.027 mmol, 68% yield) as a white solid. MS (ESI) m/z=481.31 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccnc2)C(=O)C1

Procedure:
A mixture of 3-Oxo-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 9.99 mmol) and 3-Picolyl chloride hydrochloride (1.63 g, 9.99 mmol) in DMF (20 mL) is treated by 60% NaH in mineral oil (0.80 g, 19.98 mmol) at 0° C. After completion, the reaction mixture is quenched by H2O, EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless oil; ES-MS: M+H=292.2et=4.15.
Reaction SMILES: [OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH:16]([N-]C(C)C)([CH3:18])[CH3:17].[Li+].C(Br)C=C.Cl>O1CCCC1>[OH:1][C:2]1[CH:11]([CH2:18][CH:16]=[CH2:17])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1=C(O)CCc2ccccc21
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1Cc2ccccc2C(C(=O)OC)=C1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a stirred solution of 3,4-dihydro-2-hydroxynaphthalene carboxylic acid, methyl ester (36.2 g, 177 mmol) in dry tetrahydrofuran (440 ml) at -30° C. under argon was added dropwise lithium diisopropylamide (195 ml, 2M solution, 390 mmol). Allyl bromide (24.3 ml, 284 mmol) was then added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h, then treated with hydrochloric acid (5M) to pH2-3. The resulting mixture was extracted with ethyl acetate (2×1000 ml) and the combined extracts were washed with brine (1000 ml), dried (Na2SO4) and evaporated in vacuo to give the title compound as a brown oil (46.1 g).
Reaction SMILES: [O-]O.[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C(C)C)C=CC=CC=1.C(C1C=CC=CC=1)(=[O:23])C>O>[CH3:10][C:9]([OH:23])([CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)c1ccccc1
Agent: [O-]O
Solvent: O
Product: CC(C)(O)c1ccccc1

Procedure:
In the manufacture of cumene hydroperoxide (CHP) wherein cumene is oxidized to CHP, the improvement comprising refining the cumene hydroperoxide product stream containing, in weight percents, about 80 to about 89 CHP, about 0.6 to about 1.6 water, about 0.5 to about 2.0 acetophenone, about 2 to about 15 cumene, and about 5 to about 9 dimethylbenzyl alcohol to obtain a product substantially reduced in color, water, acetophenone, and dimethylbenzyl alcohol, by subjecting said product stream to a first evaporation step at a temperature of 150° to 210° F. and pressure of 2 to 10 mm Hg, passing the residue therefrom to a second evaporation step at a temperature of about 135° to about 210° F. and a pressure of about 0.5 to about 8 mm Hg, and condensing the vapors therefrom to recover a refined cumene hydroperoxide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([Mg]Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1>[C:1]1([CH2:7][CH2:8][CH:9]([OH:10])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: O=CCCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCc1ccccc1)CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 12.8 g (95.2 mmol) of 3-phenyl-propionaldehyde in anhydrous THF (100 mL) was added dropwise at 0° C. a 1.0M solution of 100 mL (100 mmol) of phenethyl magnesium bromide in THF, and the mixture was stirred for 2 hours at 0° C. The solution was poured over saturated ammonium chloride and extracted with ether (3×150 mL). The organic phase was dried (MgSO4) and evaporated to a solid, which was subject to column chromatography (EtOAc/Hexanes, 1:9) to yield 10.0 g (22.8%) of 8a as a white solid. TLC Rf=0.5 (EtOAc/Hexanes, 1:9)
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[S:16]>C(#N)C>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[S:16])[S:10][C:6]=2[CH:5]=1
Reactant: Nc1nc2ccc(OC(F)F)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: FC(F)Oc1ccc2nc(NC(=S)n3ccnc3)sc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To 6-(difluoromethoxy)benzo[d]thiazol-2-amine (0.5 g, 2.3 mmol) in acetonitrile (15 mL) was added 1,1′-thiocarbonyldiimidazole (0.49 g, 2.8 mmol). The reaction was stirred at 70° C. overnight. The reaction was cooled to room temperature and the precipitate was filtered to yield N-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (500 mg, 1.53 mmol, 66.3% yield) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([Cl:19])[N:16]=[C:17](Cl)[C:12]=3[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][NH2:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([Cl:19])[N:16]=[C:17]([NH:22][CH3:21])[C:12]=3[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccc(Br)cc1)COC2
Agent: Cl
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(Br)cc1
Yield: 42.6 %

Procedure:
8-(4-bromophenyl)-2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation L) (500 mg, 1.389 mmol) and methanamine hydrochloride (141 mg, 2.083 mmol) were combined and purified as per Preparation Ha to give 8-(4-bromophenyl)-2-chloro-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (210 mg, 0.592 mmol, 42.6% yield). LC-MS (M+H)+=356.0. 1H NMR (500 MHz, MeOD) δ ppm 7.46 (2 H, d, J=8.24 Hz), 7.13 (2 H, d, J=8.55 Hz), 4.43-4.71 (2 H, m), 4.09 (1 H, dd, J=11.44, 4.12 Hz), 3.92-4.03 (1 H, m), 3.86 (1 H, d, J=3.05 Hz), 3.00 (3 H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][CH2:34][NH2:35])[CH2:29]1)[CH3:27]>CS(C)=O.CO>[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][CH2:34][NH:35][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: CCN1CC[C@@H](CCN)C1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CO
Solvent: CS(C)=O
Product: CCN1CC[C@@H](CCNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 130 °C
Yield: 46.8 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.2 g) and 2-((R)-1-ethylpyrrolidin-3-yl)ethylamine (Intermediate 203, 2.0 g) in DMSO (2 mL) was divided between two sealed vials and each was stirred and heated at 130° C. for 24 hours. After cooling, the combined mixture was diluted with methanol and then concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.125 g) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:53])[C:7]([S:25][C@@H:26]1[CH2:30][CH2:29][O:28][C@@H:27]1[CH2:31][NH:32][C:33](=[O:52])[C@@H:34]([NH:38]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH:35]([CH3:37])[CH3:36])=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].O>C(O)CCCC.[Pd]>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([NH:32][CH2:31][C@@H:27]1[C@H:26]([S:25][C:7]2[C@H:6]([CH3:53])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:30][CH2:29][O:28]1)=[O:52]
Reactant: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: [Pd]
Solvent: CCCCCO
Solvent: O
Product: CC(C)[C@H](N)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 20 h
Yield: 80.5 %

Procedure:
To a mixture of 1.0 g of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}-amino)butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 50 ml of 1-pentanol is added 50 ml of water followed by 0.5 g of 10% palladium-on-carbon. The reaction mixture is then hydrogenated in a Parr apparatus at 54 psi for 20 hours. The mixture is filtered through a pad of diatomaceous earth and the pad washed with an additional 40 ml of water. The filtrate is transferred to a separatory funnel, and the aqueous layer separated. The 1-pentanol layer is washed with an additional 10 ml of water. The combined aqueous layers are washed with 100 ml of ethyl acetate and lyophilized to afford 0.47 g(81%) of the desired product. MS (ES), m/z:442.3 (M+H)+, 98% area percent pure by analytical HPLC.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(OC)=C(F)C=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: COc1ccc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC3)cc1F
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F
Yield: 5.4 %

Procedure:
The title compound (0.021 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.35 g) using 3-fluoro-4-methoxybenzyl bromide (0.25 g) in place of benzyl chloride. The reaction sequence also provided 3-(4-chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H21ClFN3O, 385.14. found, m/z 386.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.47-7.42 (m, 2H), 7.06-7.02 (m, 1H), 6.90-6.86 (m, 2H), 5.29 (s, 2H), 3.84 (s, 3H), 3.35-3.29 (m, 2H), 2.94-2.92 (m, 4H), 2.88-2.85 (m, 2H), 2.80-2.77 (m, 2H). 13C NMR (125 MHz, CD3OD): 154.2, 152.2, 149.1, 148.1, 143.5, 134.2, 132.9, 131.1, 131.0, 130.5, 129.1, 123.3, 118.7, 115.0, 114.8, 114.4, 56.2, 52.4, 49.9, 28.8, 27.3.
Reaction SMILES: C[CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:27]([C:29]([OH:31])=O)[N:28]=1>>[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:27]([C:29]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH2:2][CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:31])[N:28]=1
Reactant: Nc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)c1nc(N)sc1-c1ccccc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-amino-5-phenyl-thiazole-4-carboxylic acid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([O:25][CH3:26])(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:18]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(C=Cc1ccccc1)c1ccc(I)cc1
Product: COC(=O)C(C(=O)OC)C(CC(=O)c1ccc(I)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-iodophenyl)-3-phenylprop-2-en-1-one and dimethyl malonate, dimethyl 2-(3-(4-iodophenyl)-3-oxo-1-phenylpropyl)malonate was obtained as yellowish solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]>ClCCl>[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1ccccc1
Reactant: CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1ccc(CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of valeryl chloride and aluminium chloride in dichloromethane was stirred at 0° C. for 30 minutes, and then isobutylbenzene was added. After stirring at 0° C. for 1 hour, the mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed with an aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give the object compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].C(N(CC)CC)C.[CH:22]1[N:23]=[CH:24][N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12>ClCCCl>[CH:22]1[N:23]=[C:24]([C:6]([C:5]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:7])[N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12
Reactant: c1ccn2cncc2c1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1cc(C(=O)c2ncc3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.5 g (0.053 mol) of 3-methoxy-4-nitrobenzoyl chloride and 7.8 ml (0.056 mol) of triethylamine are added to 3 g (0.025 mol) of imidazo[1,5-a]pyridine [described in J. Chem. Soc., (1955), 2834-2836] dissolved in 100 ml of 1,2-dichloroethane. The mixture is stirred at ambient temperature for 2 hours. The reaction medium is concentrated under reduced pressure and the residue is then taken up in dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in dichloromethane and purified by filtration through a bed of silica gel. After evaporation, 7.1 g of a yellow solid are collected. Melting point: 183° C.; 1H NMR (d6-DMSO): 4.01 (3H, s), 7.35-7.40 (1H, m), 7.47-7.54 (1H, m), 7.97 (1H, s), 8.06-8.11 (3H, m), 8.15 (1H, s), 9.77 (1H, d).
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>CCCCCC>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])=[N:9][CH:10]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: CC(C)(CN)CO
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(C)(CO)CNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 90 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (191 mg, 0.458 mmol) obtained in Example 54 and 3-amino-2,2-dimethylpropan-1-ol (515 mg, 5.00 mmol) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. Ethyl acetate was added to the residue. The resulting mixture was washed sequentially with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (199 mg, 0.412 mmol, 90%) as an amorphous substance.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Nc2ccccc2)cc1
Yield: 27.4 %

Procedure:
A solution of 4-(phenylamino)benzoic acid (0.048 g, 0.225 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.052 g; 0.225 mmol), HATU (0.094 g; 0.247 mmol) and N,N-diisopropylethylamine (0.097 mL; 0.563 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.024 g (27%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>C1COCC1.CCCCCC>[OH:17][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2C(F)(F)F)CC1
Reaction time: 0.67 h
Yield: 45.2 %

Procedure:
To a solution of 1-bromo-2-(trifluoromethyl)benzene (1.18 g, 5.24 mmol) in THF (20 mL) cooled at −78° C. was dropwise added a 1.60 M solution of n-butyllithium in hexane (3.4 mL). After being stirred for 40 min; a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.0 g, 5.0 mmol) in THF (3 mL) was added and the solution stirred for 1 h at −78° C. The reaction was quenched with saturated ammonium chloride. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated to give 0.78 g of a white solid which was used for the next reaction without purification. MS calculated for C17H22F3NO3: (M+H) 346; found 246.0 (M-Boc+1).
Reaction SMILES: [OH:1][C:2]1([C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][N:4]([C:6]([O:8]CC2C=CC=CC=2)=O)[CH2:3]1.CCN(C(C)C)C(C)C.[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([CH:45]=[CH:46][C:47]=1[F:48])C(F)=O>[Pd].CO>[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([C:6]([N:4]2[CH2:5][C:2]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([OH:1])[CH2:3]2)=[O:8])[CH:45]=[CH:46][C:47]=1[F:48]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
1,1-Dimethylethyl (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (60.8 mg, 0.16 mmol) and 10% Pd/C (30 mg) were taken into methanol (2 mL) and the mixture hydrogenated at ambient pressure for one hour. The suspension was then filtered through a celite pad and concentrated then dried in vacuo to a colorless solid. The solid amine was taken into THF (1 mL) followed by addition of DIPEA (42 μL, 0.24 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (63 mg, 0.16 mmol), prepared using procedures similar to those described in Reference 1, and the mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and 1 N aqueous hydrochloric acid and the organic layer washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using hexanes:ethyl acetate 3:2 as eluent afforded 1,1-dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 74% yield) as an amorphous solid. 1,1-Dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate 1H NMR (400 MHz, CDCl3): 8.53 (br s, 0.5H), 8.40 (br s, 0.5H), 7.41-7.38 (dd, 1H), 7.34-7.31 (dt, 1H), 7.17-7.14 (m, 1H), 6.86-6.79 (m, 1H), 6.63-6.587 (m, 1H), 4.24-3.90 (m, 4H), 3.37-3.23 (m, 1H), 2.90-2.80 (m, 1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (EI) for C26H29F3IN3O4: 576 (M-C4H9+).