Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[CH:6][CH:5]=1.[NH2:18][CH2:19][C@@H:20]([C:22]1[CH:33]=[CH:32][C:25]2[O:26][C:27]([CH3:31])([CH3:30])[O:28][CH2:29][C:24]=2[CH:23]=1)[OH:21].P([O-])([O-])([O-])=O>CN(C=O)C>[NH3:18].[Si:9]([O:8][C:7]1[CH:16]=[CH:17][C:4]([CH2:3][CH2:2][NH:18][CH2:19][C@@H:20]([C:22]2[CH:33]=[CH:32][C:25]3[O:26][C:27]([CH3:30])([CH3:31])[O:28][CH2:29][C:24]=3[CH:23]=2)[OH:21])=[CH:5][CH:6]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCBr)cc1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(O[Si](C)(C)C(C)(C)C)cc3)ccc2O1
Product: N
Temperature: 20 °C
Reaction time: 9.5 h
Yield: 142.6 %

Procedure:
A solution of [4-(2-bromoethyl)phenoxy](tert-butyl)dimethylsilane (479 mg) in DMF (20 ml) under nitrogen was treated with (1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (678 mg) and the mixture was stirred at 20° C. for 9.5 h. Phosphate buffer solution (pH 6.5) was added and the mixture was extracted with EtOAc. The extract was washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by SPE (10 g). Elution with DCM then DCM-EtOH-0.880 ammonia solution (300:8:1) then (150:8:1) gave the title compound (991 mg). LCMS RT=3.13 min.
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH:7](Cl)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)Cl>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH:7]([C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1Cc2cc(OC)ccc2SC(Cl)C1
Reactant: COc1ccccc1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N1Cc2cc(OC)ccc2SC(c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
The above-mentioned 4-acryloyl-2-chloro-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.3 g) and anisole (1.1 g) were dissolved in methylene chloride (50 ml) and stannic chloride (2.8 g) was added thereto and agitated at room temperature for 2 hours. To the reaction mixture water was added and extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and thereafter the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 50 g) and eluted with a mixed solvent of n-hexane (70 parts)+ethyl acetate (30 parts) to give 4-acryloyl-2-[4-methoxyphenyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.7 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.N[CH2:13][C:14]1C=C(C=CC=1)CN(CC1NC2C=CC=CC=2N=1)C1C2N=CC=CC=2CCC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:13]([O:9][C:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=1[CH3:11])=[O:10])[CH3:14]
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1c(C)ncnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F: A solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid from above (prepared as described in patent application PCT/US00/11632) (42 mg, 0.28 mmol), (3-aminomethyl-benzyl)-(1 H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (100 mg, 0.25 mmol), HOBT (38 mg, 0.28 mmol) and 4-methylmorpholine (40 μL, 0.38 mmol) in DMF (0.8 mL) was flushed with N2. EDCI (54 mg, 0.28 mmol) was added and the mixture was stirred at room temperature overnight. Purification of the colorless syrup (150 mg) by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) afforded AMD11084 (80 mg, 60%) as a white foam. 1H NMR (CDCl3) δ 1.64-1.77 (m, 1H), 1.91-2.08 (m, 2H), 2.18-2.34 (m, 1H), 2.37 (s, 6H), 2.69-2.91 (m, 2H), 3.73 (s, 2H), 3.80 (d, 1H, J=16.5 Hz), 400 (d, 1H, J=16.5 Hz), 4.07-4.13 (m, 1H), 4.69 (d, 2H, J=5.7 Hz), 6.53 (t, 1H, J=5.7 Hz), 6.96-7.10 (m, 3H), 7.16-7.22 (m, 2H), 7.29-7.31 (m, 2H), 7.40-7.45 (m, 3H), 8.64 (d, 1H, J=3.6 Hz), 8.81 (s, 1H); 13C NMR (CDCl3) δ 21.71, 22.28, 24.38, 29.55, 44.29, 49.22, 55.11, 61.90, 111.12, 118.82, 121.68, 122.78, 127.32, 128.67, 129.09, 129.24, 130.48, 135.22, 137.66, 137.83, 140.30, 147.22, 156.42, 157.60, 157.91, 163.43, 166.96. ES-MS m/z 532.4 (M+H). Anal. Calcd. for C32 H33N7O•0.4CH2Cl2: C, 68.80; H, 6.02; N, 17.33. Found: C, 68.56; H, 6.09; N, 17.34.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@@H:7]([O:20]CCOCCOCCOCC(O)=O)[C@@H:6]1[NH:34][C:35](=[O:37])[CH3:36])(=O)C.Cl.C(OC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)CCCCN)C1C=CC=CC=1.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[OH:20][CH:7]1[O:8][C@H:9]([CH2:15][OH:16])[C@H:10]([OH:11])[C@H:5]([OH:4])[C@H:6]1[NH:34][C:35]([CH3:36])=[O:37]
Reactant: CC(=O)N[C@H]1[C@H](OCCOCCOCCOCC(=O)O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: NCCCC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 142.2 %

Procedure:
The above prepared (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid (2.820 g, 5.246 mmol) and (S)-6-amino-2-((S)-2,6-diamino-hexanoylamino)-hexanoic acid benzyl ester hydrochloride (preparation see below, 0.829 g, 1.749 mmol) were dissolved in a mixture of 32 mL of CH2Cl2 and 3.2 mL of DMF, treated successively with Hünig's base (2.096 ml, 12.25 mmol), 1-hydroxy-7-azabenzotriazole (0.714 g, 5.248 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (1.006 g, 5.248 mmol), and stirred over night at ambient temperature. All volatiles were removed i.V., and the crude reaction mixture purified by preparative HPLC (38 runs, Gemini, 5μ, C18) to give after lyophilization 1.650 g of the title product as white powder. MS (ISP): 1945.8 [M+Na]+. NMR (600 MHz, DMSO).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([CH2:15][N:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=4)[CH2:29][CH2:28]3)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)c2nc(CCl)cn2c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CCN(Cc3cn4cc(C(F)(F)F)cc(Cl)c4n3)CC2)cc1
Temperature: 82.5 °C
Reaction time: 2.25 h
Yield: 64.8 %

Procedure:
A mixture of 8-chloro-2-(chloromethyl)-6-trifluoromethylimidazo[1,2-α]pyridine (0.341 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.264 g), triethylamine (Aldrich; 0.21 mL), and ethylene glycol (2 mL) is stirred for 2.25 h at 80-85° C. After cooling, the mixture is partitioned between water and dichloromethane and the combined inorganic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (2/98) and the appropriate fractions combined, concentrated, and crystallized from ether/hexane to give 0.339 g of the title compound; mp 91-97° C.; MS m/z 412, 414; IR (mineral oil) 1322, 1161, 1153, 1512, 1171 cm-1 ; 1H NMR (CDCl3) δ2.76, 3.15, 3.87, 6.88, 6.96, 7.41, 7.75, 8.41.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[O:11]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1ccccc1Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (6.82 g, 53.71 mmol) in CH2Cl2 (250 mL) at -78° C., was added dimethylsulfoxide (8.76 g, 112.1 mmol) dropwise. The mixture was stirred for 5 mins. A solution of crude 2-phenoxybenzyl alcohol from above in CH2Cl2 (20 mL) was added dropwise. Upon completion of addition, the reaction was stirred for 20 mins at -78° C. Triethylamine (23.58 g, 233.5 mmol) was then added dropwise. The cooling bath was removed and the reaction allowed to warm to room temperature. It was then diluted with brine (250 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (2×250 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 20:80) to afford 7.65 g (83% over the two steps) of 2-phenoxybenzaldehyde as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:17][C:16]=2[F:34])=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[NH:10][NH2:11])(=[O:3])[NH2:2].[CH:35]([O-])([O-])OC>CC(N(C)C)=O>[C:1]([C:4]1[C:9]2[N:8]([CH:35]=[N:11][N:10]=2)[C:7]([S:12][CH3:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]2)=[CH:17][C:16]=1[F:34])(=[O:3])[NH2:2]
Reactant: COC([O-])[O-]
Reactant: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Solvent: CC(=O)N(C)C
Product: CSc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(C(N)=O)c2nncn12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 28D (240 mg, 0.5 mmol) in dimethylacetamide (2 mL) was added methyl orthoformate (2 mL). The mixture was stirred at ambient temperature for 1 hour and at 60° C. for 4 hours. After cooling to ambient temperature, petroleum 9/1 ether/ethyl acetate (50 mL) was added and the precipitate was filtered. The solid was washed with petroleum ether and dried under vacuum to give the title compound. MS: 503 (M+H+).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.O.[NH2:37][NH2:38].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:32][C:31]([F:33])([F:34])[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:38][N:37]=1
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3cccc(C(F)(F)F)c3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethylphenyl)-3-(3-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one (740 mg, 1.5 mmol) produced in Synthesis Example 15 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 291 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(3-trifluoromethylbenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (364 mg, yield 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26]([C:28]2[C:29](=[O:41])[N:30]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:31]([CH3:34])[C:32]=2[CH3:33])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][C:21]3([OH:24])[CH2:23][CH2:22]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:42]([NH:49][CH2:50][C:51](O)=[O:52])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:45]([O:44][C:42]([NH:49][CH2:50][C:51]([O:24][C:21]1([CH2:20][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:25][C:26]([C:28]5[C:29](=[O:41])[N:30]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:31]([CH3:34])[C:32]=5[CH3:33])=[O:27])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:22][CH2:23]1)=[O:52])=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC5(OC(=O)CNC(=O)OC(C)(C)C)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-((1-hydroxycyclopropyl)methoxy)-quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (100 mg, 0.18 mmol), N-Boc-glycine (63 mg, 0.36 mmol, Alfa), and DMAP (3 mg, 0.018 mmol, Aladdin) in 10 mL of dichloromethane was added DCC (189 mg, 0.9 mmol, Aldrich) slowly at 0° C. After stirring at rt overnight, the mixture was filtered and washed with dichloromethane (10 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (PE: EtOAc=1:6) to give the title compound as a yellow solid (100 mg, 78%).
Reaction SMILES: [C:1]([CH:5]1[C:11](=[O:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[ClH:17]>CO.C(O)C>[ClH:17].[C:1]([CH:5]1[CH:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1C(=O)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COC(=O)C1C(O)C[C@@H]2CC[C@H]1N2C
Reaction time: 4 h

Procedure:
To a solution of the 2-carbomethoxy-3-tropanone obtained in example 4 (17 g, 85 mmol) in 750 ml methanol cooled to -35° C. was added sodium borohydride (17 g, 450 mmol) and the mixture was stirred for 4 hours. The cooled solution was quenched by slow addition of concentrated hydrochloric acid (40 ml) and the mixture was concentrated in vacuo. Water (400 ml) was added and the pH was adjusted to 3 by addition of concentrated hydrochloric acid. After having washed the water phase three times with diethyl ether pH was adjusted to 11 by addition of concentrated ammonium hydroxide and the water phase was extracted three times with methylene chloride. Concentration in vacuo yielded oil which was dissolved in ethanol and added concentrated hydrochloric acid followed by concentration in vacuo. Freeze drying of the residue yielded the title compound as an amorphous product.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:13])[C:10](C)=[CH2:11].C(OCC)(=O)C(C)=C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:5][CH2:6][CH2:7][CH2:8][CH:3]([CH2:4][O:14][C:9]([CH:10]=[CH2:11])=[O:13])[CH2:2][CH3:1].[CH3:18][CH2:17][CH2:16][CH2:15][O:14][C:9]([CH:10]=[CH2:11])=[O:13]
Reactant: C=C(C)C(=O)OCCCC
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCC(CC)CCCC
Product: C=CC(=O)OCCCC
Temperature: 110 °C
Reaction time: 3 h

Procedure:
An acrylic copolymer resin was prepared by feeding 150 parts of toluene into a 500-ml 4-necked flask equipped with a cooling tube, stirrer, and thermometer, heating it to 110° C., adding styrene 40 parts, n-butyl methacrylate 40 parts, ethyl methacrylate 120 parts, methacylic acid 12 parts, benzoyl peroxide 4 parts, and toluene 60 parts spending 3 hours under an inert gas atmosphere, and further heating for 6 hours. This copolymer (designated as acrylic resin-A) was found to have nonvolatile matter content 49.5%, Tg 52° C., polymer acid value 15, and number average molecular weight 28,000.
Reaction SMILES: [Mg].II.F[C:5]1C=C(Br)C=CC=1OC(F)(F)F.[CH3:17][O:18][C:19](=[O:27])[CH:20]([N:22]1[N:26]=[N:25][CH:24]=[N:23]1)[CH3:21].Cl>O1CCCC1.O>[CH2:17]([O:18][C:19](=[O:27])[CH:20]([N:22]1[N:26]=[N:25][CH:24]=[N:23]1)[CH3:21])[CH3:5]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: COC(=O)C(C)n1ncnn1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)n1ncnn1
Yield: 43.5 %

Procedure:
Magnesium turnings (1.22 g) and iodine (1 crystal) were added to dry tetrahydrofuran (10 ml) under a nitrogen atmosphere. A solution of 3-fluoro-4-trifluoromethoxybromobenzene (12.95 g) in dry tetrahydrofuran (30 ml) was placed in a dropping funnel. About 10% of this was added to the mixture, and the Grignard reaction began immediately. The rest of the mixture was added dropwise with stirring, and the temperature rose until the solvent was at reflux. After the addition was complete the mixture was allowed to cool, then a solution of methyl-2-(2H-tetrazol-2-yl)propionate (3.9 g) in dry tetrahydrofuran (10 ml) was added with stirring. An exotherm was noted, and the reaction was allowed to stir at room temperature for 30 minutes. The mixture was then poured into water (100 ml). The mixture was acidified by adding 3M hydrochloric acid (100 ml) and then extracted with diethyl ether (3×100 ml). The combined ethereal extracts were dried over anhydrous sodium sulphate and evaporated to a brown oil (10 g). This was chromatographed on silica gel eluting with 4:1 hexane/ethylacetate to give an oil (1.85 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][C@@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O[C@@H]1CCOC1
Product: Brc1ccc(O[C@@H]2CCOC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and (R)-3-hydroxytetrahydrofuran by the method of Example 10 (b).
Reaction SMILES: [CH2:1]([C:3]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([OH:14])[CH:7]=1)=[CH:4][CH3:5])[CH3:2].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CC(C)=O.CN(C=O)C>[CH2:20]([O:19][C:17]([C:16]1[O:14][C:8]2[CH:7]=[C:6]([C:3]([CH2:1][CH3:2])=[CH:4][CH3:5])[CH:13]=[CH:12][C:9]=2[CH:10]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CC=C(CC)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC=C(CC)c1ccc2cc(C(=O)OCC)oc2c1
Yield: 76.9 %

Procedure:
4-(1-Ethyl-propenyl)-2-hydroxy-benzaldehyde (9.00 g, 47.3 mmol) and ethyl bromoacetate (9.88 g, 59.1 mmol) and K2CO3 (13.1 g, 94.6 mmol) in acetone (100 mL) followed by DBU (mL) and DMF (40 mL) are reacted analogous to Example 30-B to give the title compound (9.40 g, 77%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 46a (0.6 g, 1.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.6 g, 89%).
Reaction SMILES: C=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.CN(C)CCCN=C=NCC.C1(CC(O)=[O:29])C=CC=CC=1.C[N:32]([CH:34]=[O:35])C>>[OH:29][NH:32][C:34](=[O:35])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CN(C)C=O
Reactant: C=Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: O=C(Cc1ccccc1)NO
Reaction time: 8 h
Yield: 39 %

Procedure:
To a suspension of the 4-(methyl-O-methylhydroxylamine)-2-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene)resin (0.10 g, 0.14 mmol) in dry DMF (2 ml) is added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.08 g, 0.42 mmol, 3 eq.). To the mixture is then added phenylacetic acid (0.06 g, 0.42 mmol, 3 eq.). The mixture is shaken overnight. The resin is filtered and washed with DMF (×5), THF: H2O (3:1, ×5), THF (×3), MeOH (×3) and DCM (×3). To the resin is added TFA (1 ml) and DCM (1 ml) and the mixture shaken for 1 hour. The mixture is filtered into a tared vial and the resin washed with DCM (×2) and toluene (×2). The combined filtrates are evaporated in vacuo to yield N-hydroxy-phenyl-acetamide (0.0084 g, 39%). LCMS gives 151 [M+].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].C1[C:20]([CH2:21][C@@H:22]([NH2:26])[C:23]([OH:25])=[O:24])=CC=C(OC2C=CC(O)=CC=2)C=1.C([O-])([O-])=[O:36].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:26][C@H:22]([C@@H:21]([OH:36])[CH3:20])[C:23]([OH:25])=[O:24])=[C:3]([CH3:14])[C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: N[C@H](Cc1ccc(Oc2ccc(O)cc2)cc1)C(=O)O
Reactant: O=C([O-])[O-]
Reactant: Cc1c(F)ccc(C#N)c1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1C(F)(F)F
Temperature: 75 °C
Reaction time: 24 h
Yield: 26.9 %

Procedure:
4-fluoro-3-methyl-2-(trifluoromethyl)benzonitrile (1.0 g, 4.92 mmol) and D-theronine (703 mg, 90 mmol) were added to DMSO (15 mL). K2CO3 (3.26 g) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly in to a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to give the crude product. The crude product was chromatographed with a gradient of hexanes/EtOAc and then with EtOAc, 100% to give the final product (400 mg). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.62 (d, J=9 Hz, 1H), 6.98 (d, J=9 Hz, 1H), 5.52 (d, J=9 Hz, 1H), 4.52 (m, 1H), 4.32 (m, 1H), 2.35 (s, 3H), 1.35 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([O:20][CH3:21])[C:15](OCC)=[O:16])=[C:4]([CH3:24])[CH:3]=1.CO.O.[NH2:28][NH2:29]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([O:20][CH3:21])[C:15]([NH:28][NH2:29])=[O:16])=[C:4]([CH3:24])[CH:3]=1
Reactant: CCOC(=O)C(OC)c1ccccc1COc1ccc(Cl)cc1C
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(C(=O)NN)c1ccccc1COc1ccc(Cl)cc1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To 1.05 g (3 mmol) of ethyl 2-(4-chloro-2-methylphenoxymethyl)phenyl-2-methoxyacetate was added 6 ml of methanol and 0.75 g (15 mmol) of hydrazine monohydrate and stirred at 60° C. for 16 hours. After completion of the reaction, 100 ml of brine was added and extracted twice with 70 ml of dichloromethane. The extract was dried over anhydrous magnesium and concentrated under reduced pressure to give 2-(4-chloro-2-methylphenoxymethyl)phenyl-2-methoxyacetic acid hydrazide (0.93 g, 92.6%) as colorless oil.