Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:8][CH:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[N:26]4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:6]1)=[N+]=[N-]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][CH2:4][C@@H:5]1[CH2:6][C@H:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[N:26]4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:8]1
Reactant: [N-]=[N+]=NCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: NC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)C1
Reaction time: 16 h

Procedure:
3-[3-(Azidomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine (0.81 mmol, 360 mg) was dissolved in hot ethanol (15 mL) and charged with Lindlar catalyst (0.14 mmol, 362 mg). The reaction mixture was purged with N2, evacuated and filled with H2. The reaction mixture was stirred under H2 for 16 h. The suspension was filtered through celite and the solvent was removed under reduced pressure. Part of the crude material (200 mg out of 300 mg) was purified by silica gel flush chromatography (Jones Flashmaster, 5 g/70 mL cartridge) eluting with 3% MeOH (7 N NH3) in DCM. The final compound was recrystallized from EtOAc and hexane to generate the desired product as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.42-8.41 (m, 1H), 8.27 (dd, J=8.0 Hz, 0.4 Hz, 1H), 8.21-8.19 (m, 2H), 7.95-7.92 (m, 3H), 7.57-7.48 (m, 3H), 7.19 (d, J=4.0 Hz, 1H), 7.11 (d, J=4.0 Hz, 1H), 5.20 (b, 2H), 3.73-3.69 (m, 1H), 2.81 (d, J=7.2 Hz, 2H), 2.66-2.62 (m, 2H), 2.58-2.48 (m, 1H), 2.36-2.30 (m, 2H); MS (ES+): m/z 421.13 (40) [MH+]; HPLC: tR=1.69 min (OpenLynx, polar 5 min).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH:5]([OH:8])[CH2:6][CH3:7].[CH2:9](Br)[CH:10]=[CH2:11]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:11]([O:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH3:3])[CH:10]=[CH2:9]
Reactant: CCC(O)CC
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: C=CCOC(CC)CC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
NaH (60% in oil, 2.76 g, 68.3 mmol) was added to a solution of 3-pentanol (4 g, 45.5 mmol) in tetrahydrofuran (20 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 10 min at 0° C. followed by addition of allyl bromide (8.2 g, 68.3 mmol) and tetrabutylammonium iodide (60 mg, 0.016 mmol). The resulting mixture was stirred for 16 hrs at 23° C. before being quenched by addition of a saturated aqueous ammonium chloride solution. The organic layer was extracted with trichloromethane, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Distillation at atmospheric pressure yielded 3-(allyloxy)pentane (compound S1, 4.8 g, yield 82%, boiling point 115° C. to 120° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].C(N(CC)CC)C.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[S:25](Cl)(=[O:27])=[O:26]>CC(C)=O>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[S:25]([O:9][C:4]1[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([NH2:1])[CH:3]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(O)cc1N
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccc(OS(=O)(=O)c2c(F)cccc2F)cc1N
Temperature: 20 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
To a solution of 2 g of 3,4-diaminophenol in 150 cm3 of acetone are added 2.264 cm3 of triethylamine and 3.425 g of 2,6-difluorobenzenesulfonyl chloride. The reaction medium is stirred at a temperature in the region of 20° C. overnight. The insoluble material is filtered off and rinsed with three times 50 cm3 of acetone, and the filtrate is evaporated to dryness under reduced pressure (3.5 kPa). The residue is taken up in 300 cm3 of dichloromethane, washed with three times 50 cm3 of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)], 650 mg of 3,4-diaminophenyl 2,6-difluorobenzenesulfonate are obtained in the form of a black resin, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].CC(C)(C)CCN.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39](N)=[O:40]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:39](=[O:40])[CH2:38][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:18]1=[O:17]
Reactant: NC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: Cc1cccc(C)c1N
Agent: CC(C)(C)CCN
Product: Cc1cccc(C)c1NC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12.49 and making non-critical variations using 2,6-dimethylaniline to replace 3,3-dimethylbutylamine, dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)acetamide was obtained (67%) as a colorless solid: mp 261-262° C.; 1H NMR (300 MHz, DMSO-d6) δ9.66 (s, 1H), 7.30 (dd, J=7.7, 7.7 Hz, 1H), 7.16-6.98 (m, 6H), 6.51 (s, 1H), 6.37 (s, 1H), 4.75 (ABq, 2H), 4.67-4.52 (m, 2H), 4.49-4.40 (m, 2H), 2.90 (dd, J=8.6, 8.6 Hz, 2H), 2.12 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ177.7, 165.4, 161.5, 160.9, 143.0, 135.7, 135.0, 132.9, 128.9, 128.2, 127.1, 123.9, 123.4, 121.3, 120.2, 119.7, 109.3, 92.8, 80.2, 72.5, 57.4, 43.0, 28.8, 18.6, 15.6; MS (ES+) m/z 441.2 (M+1).
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:8]([O:10]CC(Cl)(Cl)Cl)=O)=O.[C:24]1([C:30]2[N:34]=[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:24]1([C:30]2[N:34]=[C:33]([N:35]3[CH2:40][CH2:39][N:38]([C:8]([NH:7][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:37][CH2:36]3)[S:32][N:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixed solution of bis(2,2,2-trichloroethyl)pyridin-3-ylimidodicarbonate (271 mg, 0.610 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.211 ml, 1.22 mmol) in dimethyl sulfoxide (2 ml) was stirred at 70° C. for 3 hours and further stirred at 80° C. for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 106 mg (47.5%) of the desired product as a solid.
Reaction SMILES: C(=O)([O-])O.[Na+:5].CC1(C)CC(=O)CC(=O)C1.P(OCC)(OCC)OCC.C([O:29][C:30]([C:32]1[N:36]2[C:37](=[O:42])[C@H:38]([C@H:39]([OH:41])[CH3:40])[C@H:35]2[C@@H:34]([CH3:43])[C:33]=1[S:44][C@H:45]1[CH2:49][NH:48][C:47](=[S:50])[CH2:46]1)=[O:31])C=C>O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(O)C>[Na+:5].[NH:48]1[CH2:49][C@H:45]([S:44][C:33]2[C@H:34]([CH3:43])[C@@H:35]3[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:36]3[C:32]=2[C:30]([O-:31])=[O:29])[CH2:46][C:47]1=[S:50]
Reactant: C=CCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: O
Solvent: CCO
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CNC(=S)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of sodium hydrogen carbonate (84 mg) in water (1 ml) is added dimedone (84 mg), and the mixture is dissolved by treating with ultrasonics. Thereto is added ethanol (8 ml), and further treated with ultrasonics for five minutes. To the mixture are added palladium diacetate (11 mg), triethyl phosphite (0.06 ml) and (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (383 mg) under nitrogen atmosphere, and the mixture is stirred at 35°-38° C. for one hour, and stirred at 20° C. for 10 minutes, and then stirred at 5° C. for 20 minutes. The precipitated crystals are collected by filtration to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (157 mg). The mother liquor is concentrated under reduced pressure to remove the ethanol, and thereto is added water (20 ml). The mixture is washed five times with chloroform (20 ml), and the aqueous layer is subjected to lyophilization to give the above sodium salt (168 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[Li+].C[Si]([N-:54][Si](C)(C)C)(C)C.[NH4+].[Cl-]>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].O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:54])[CH:7]=3)=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10]2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-n2nc(C(F)(F)F)cc2-c2ccnc(Cl)c2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(F)cc2)ccn1
Temperature: 65 °C
Yield: 94.9 %

Procedure:
2-Chloro-4-[2-(4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-pyridine (120 mg, 0.35 mmol), Pd2(dba)3 (32 mg, 0.04 mmol) and biphenyl-2-yl-dicyclohexyl-phosphane (32 mg, 0.09 mmol) are mixed in a reaction vial and dry THF (2.0 mL) is added. Then Argon is bubbled through the solution for 5 min and 1.0 M LiHMDS (0.88 mL, 0.88 mmol) in THF is added. The reaction vial is sealed and heated at 65° C. for 16 hrs. More Pd2(dba)3 (32 mg, 0.04 mmol), biphenyl-2-yl-dicyclohexyl-phosphane (32 mg, 0.09 mmol) and 1.0 M LiHMDS (0.88 mL, 0.88 mmol) in THF are added and the reaction mixture is heated at 65° C. for another 5 hrs. Then saturated NH4Cl solution (20 mL) is added along with water (20 mL). The mixture is extracted with EtOAc (3×30 mL) and the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 107 mg of product.
Reaction SMILES: [CH2:1]([C:4]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]2[CH:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:35]([O:37][C:38]([CH2:40][C:41](O)=[O:42])=[O:39])[CH3:36]>>[CH2:1]([C:4]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]2[CH:8]([C:12]([O:14][CH3:15])=[O:13])[N:9]([C:41](=[O:42])[CH2:40][C:38]([O:37][CH2:35][CH3:36])=[O:39])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)CC(=O)O
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2

Procedure:
Methyl 2-n-propyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-4-carboxylate and ethoxycarbonylacetic acid are treated in the same manner as in Example 8-(1) to give methyl 2-n-propyl-5-ethoxycarbonylacetyl-3-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([O:31][CH3:32])[CH:8]=1)(=[O:5])=[O:4].C(O)(=[O:37])C.C(O)(=O)C.IC1C=CC=CC=1.C(O)(=O)C.C(OC(=O)C)(=O)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:34][C:2]([F:33])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]([O:31][CH3:32])[C:10]([C:13]2[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]3[CH2:21][C:22]([CH3:28])([CH3:29])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[CH:17][CH:18]=2)=[C:11]([OH:37])[CH:12]=1)(=[O:4])=[O:5]
Reactant: CC(=O)O
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: Ic1ccccc1
Product: COc1cc(OS(=O)(=O)C(F)(F)F)cc(O)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 50 °C

Procedure:
A mixture of 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (2.6 g, 5.17 mmol), Pd(OAc)2 (58 mg, 0.259 mmol), and iodobenzene diacetate (2.33 g, 7.24 mmol) in 1:1 acetic acid/acetic anhydride (42 mL) was heated at 50° C. for 8 h. The mixture was cooled to RT and concentrated under reduced pressure. Flash chromatography (10-100% EtOH in DCM, followed by 7:1 EtOH/7 N ammonia in MeOH elution) provided a mixture of the title compound and the corresponding acetate (3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(((trifluoromethyl)sulfonyl)oxy)phenyl acetate). After concentration, the mixture was taken up in methanol and heated at 70° C. for 4 h. The solvent was evaporated to provide 3-hydroxy-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoro-methanesulfonate as a tan-colored solid (1.25 g). MS (M+1)=519.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.08 (d, J=10.1 Hz, 1H), 7.23 (d, J=10.1 Hz, 1H), 6.57 (s, 2H), 5.16 (t, J=12.1 Hz, 1H), 3.89 (s, 3H), 3.02 (s, 3H), 1.69-1.77 (m, 2H), 1.56-1.67 (m, 2H), 1.41 (s, 6H), 1.27 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(OCC)c1
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A 500 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with 3-ethoxyphenol (20.4 g, 148 mmol), K2CO3 (28.5 g, 222 mmol), and DMF (250 mL). To the resultant solution was added ethyl bromoacetate (27.1 g, 18.0 mL, 162 mmol) and the mixture stirred overnight. The solids were filtered off and rinsed with EtOAc (500 mL). The filtrate was washed with saturated aqueous NH4Cl (2×250 mL), H2O (2×250 mL), and brine (200 mL), filtered through phase separation paper, and concentrated in vacuo to give 33.6 g of ethyl 3-ethoxyphenoxyacetate as a colorless oil (100%). 1H NMR (60 MHz, CDCl3): δ 7.2-6.9 (m, 1H), 6.6-6.3 (m, 3H), 4.6 (s, 2H), 4.2 (qt, 2H), 4.0 (qt, 2H), 1.4 (t, 3H), 1.3 (t, 3H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 98% with a retention time of 5.3 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]=O)=[CH:7]2)([O-:3])=[O:2].[Cl-].[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH:19]=[CH:13][C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2
Reactant: O=Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Clc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: O=[N+]([O-])c1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1

Procedure:
Reaction of the aldehyde (904) prepared as described in example 454 with 2-chlorobenzyltriphenylphosphonium chloride using the procedure described in example 37(at room temperature) gave the diene (905) as a mixture of E/Z isomers as a yellow solid (95%). Crystallisation from aqueous methanol yielded the pure E-isomer as yellow needles (80%), mp 230–232° C. 1H NMR δ [(CD3)2SO] 12.28 (br s, 1H), 8.55 (d, J=2.3 Hz, 1H), 8.03 (dd, J=9.1, 2.3 Hz, 1H), 7.91 (dd, J=7.8, 1.5 Hz, 1H), 7.32–7.61 (m, 6H), 6.92 (s, 1H). Found: C, 64.59; H, 5.68; N, 9.49. C16H11ClN2O2 requires C, 64.33; H, 5.68; N, 9.49.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][NH:44][CH3:45]>>[CH3:43][N:44]([CH3:45])[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:37]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CNC
Product: COc1cc(C(=O)N(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with dimethylamine to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylcarbamoyl-2-methoxy-phenyl)-amide. MS (ES+) m/z calcd. for C33H35Cl2F2N4O3: [(M+H)+]: 643. found: 643.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].O1CCOCC1.[Br:18]N1C(=O)CCC1=O>O>[Br:18][C:3]1[C:2]([OH:1])=[C:9]([O:10][CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C=O)c(Br)c1O
Reaction time: 0.5 h
Yield: 75 %

Procedure:
3-Hydroxy-4-methoxybenzaldehyde (200 g, 1.31 mol), dioxane (1000 ml) and water (400 ml) were mixed, and N-bromosuccinimide (245.7 g, 1.38 mol) was added over 10 minutes. After 60 and 70 minutes, N-bromosuccinimide was further added in an amount of 16.4 g (92.1 mmol) and 7.02 g (39.4 mmol), respectively, and the mixture was further stirred for 30 minutes. Water (1600 ml) was added, and the precipitated crystals were collected by filtration. The crystals were washed with water (1000 ml) to give 2-bromo-3-hydroxy-4-methoxybenzaldehyde (227.1 g, 74.8%) as pale-red crystals.
Reaction SMILES: O1CCOC1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]=[C:14]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.Cl.[CH3:31][OH:32]>>[CH2:28]([N:25]1[CH2:26][CH2:27][N:22]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[C:12]([C:7]3[CH:8]=[CH:9][C:10]([CH:31]=[O:32])=[CH:11][CH:6]=3)[N:13]=2)[CH2:23][CH2:24]1)[CH3:29]
Reactant: CO
Reactant: CCN1CCN(c2nc(-c3ccccc3C3OCCO3)cc3ccccc23)CC1
Agent: Cl
Product: CCN1CCN(c2nc(-c3ccc(C=O)cc3)cc3ccccc23)CC1

Procedure:
3-[(1,3-Dioxolan-2-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline (4.50 g) was dissolved in methanol (50 ml), a 1N hydrochloric acid (50 ml) was added thereto, and then the mixture was reacted at 50° C. for 1 hr. The reaction solution was evaporated, basified with sodium carbonate, and extracted with ethyl acetate. The resulting organic layer was washed with water and brine in this order, dried and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 3.62 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:28].[K+]>C(#N)C.O.C(OCC)(=O)C>[I:28][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1]
Reactant: [I-]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To a stirred solution of 2-methyl-4-nitroaniline (500 mg, 3.286 mmol) in acetonitrile and water were added p-toluenesulfonic acid monohydrate (1.875 g, 9.858 mmol), sodium nitrite (453 mg, 6.572 mmol) and potassium iodide (1.363 g, 8.215 mmol). The reaction mixture was stirred for 4 h at room temperature. The mixture dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to give 1-iodo-2-methyl-4-nitrobenzene (812 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH:20]2[CH2:23][N:22]([CH:24]([CH3:26])[CH3:25])[CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH:7]=1.[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:1].[ClH:28].[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH:20]2[CH2:21][N:22]([CH:24]([CH3:26])[CH3:25])[CH2:23]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CN(C(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(C)C)C1

Procedure:
tert-Butyl {1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}carbamate (19 mg, 0.048 mmol) was treated with 4.0 M HCl in dioxane (60 μL, 0.24 mmol) in methylene chloride (50 μL) at room temperature for 2 hours. The resultant mixture was concentrated to dryness to give 1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethanamine dihydrochloride. A mixture of the HCl salt, 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (20 mg, 0.072 mmol, from Example 108, Step 1) and DIPEA (42 μL, 0.24 mmol) in ethanol (0.3 mL) was heated at 100° C. overnight. The mixture was treated with 6.0 M HCl in water (80 μL, 0.5 mmol) at room temperature for 10 min and then purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C21H28ClN6O (M+H)+: m/z=415.2. found: 415.1.
Reaction SMILES: [C:1]([O:8]CC)(=O)[CH2:2][CH2:3][C:4]([CH3:6])=O.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>[Pd]>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][N:15]1[CH:4]([CH3:6])[CH2:3][CH2:2][C:1]1=[O:8]
Reactant: CCOC(=O)CCC(C)=O
Reactant: CN(C)CCN
Agent: [Pd]
Product: CC1CCC(=O)N1CCN(C)C
Temperature: 150 °C
Reaction time: 6 h

Procedure:
To a 600-mL Hastelloy® C-276 autoclave reactor (Parr Model 2302 HC) equipped with a gas entrainment turbine impellor and electrical heating mantle was added 150.0 g (1.04 mol) ethyl levulinate, 192.6 g (2.18 mol) N,N-dimethylethylenediamine, and 7.5 g ESCAT® 142 5% Pd/C catalyst. The reactor was purged first with nitrogen and then hydrogen, and then pressurized with 50 psig (0.4 MPa) hydrogen and stirred at 600 rpm while heating the reaction mixture to 150° C. On reaching this reaction temperature, the reactor was further pressurized to 1000 psig (7.0 MPa) with hydrogen and maintained at this pressure by adding additional hydrogen as required for the duration of the reaction. After 6 hours at these conditions, the reactor was cooled and vented, and the liquid reaction mixture was recovered for product isolation. The crude mixture was filtered through a glass frit via aspirator vacuum to remove the catalyst followed by removal of byproduct ethanol and unreacted N,N-dimethylethylenediamine in vacuo. The remaining contents were fractionally distilled with a 20-cm Vigreaux column under high vacuum (˜0.05 mmHg) to give 136.5 g water-white product at 85° C. in 77% isolated yield. Product purity was >99% as determined by GC/MS (HP-6890 equipped with MSD).