Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][Cl:13].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1COCC1>[C:15]([NH:9][CH2:10][C@H:11]([OH:14])[CH2:12][Cl:13])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H](O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H](O)CCl
Reaction time: 0.08 h

Procedure:
Triethylamine (10.5 ml, 75.3 mmol, 1.11 eq) is added to a slurry of (S)-1-amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1, 9.938 g, 68.059 mmol) in THF (80 ml) at −40° and the mixture stirred for 5 min at −40°. Acetic anhydride (6.78 ml, 71.86 mmol, 1.056 eq) is then added at −40° and the mixture allowed to warm to 20-25° over 1.5 hrs. The precipitate is removed by filtration with reduced pressure and washed with THF. The filtrate is treated with magnesol (5.69 g), which is removed by filtration with reduced pressure and washed with THF (2×60 ml). The filtrate is then concentrated under reduced pressure. The concentrate is purified by flash chromatography (silica gel; eluting with a gradient of 75-100% ethyl acetate/cyclohexane) to give the title compound, NMR (CDCl3) 2.03, 3.32, 3.50-3.57, 3.55, 3.91-4.13, 5.01 and 7.09 δ; CMR (CDCl3) 28.00, 43.31, 46.52, 70.65 and 172.40 δ; MS (CI, NH3), M/Z (relative intensity), 171 (41.6), 169 (100), 154 (22.4), 152 (48.1); [α]26D=7.44 (c=1.00, H2O).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Cl)/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:28][CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: ClC/C=C/c1ccccc1
Product: O=c1c2sc3ccccc3c2n(CC=Cc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with trans-cinnamyl chloride and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.24 (s, 1H); 5.25 (s, 1H); 6.51-6.67 (m, 2H); 7.21 (dd, J=7 Hz, 1H); 7.28 (dd, J=8 Hz, 2H); 7.40 (d, J=7 Hz, 2H); 7.53 (dd, J=8 Hz, 1H); 7.61 (dd, J=8 Hz, 1H); 8.16 (d, J=8 Hz, 1H); 8.25 (d, J=8 Hz, 1H), 11.00 (br s, 1H); Ret. time=2.79 min., m/z=350.0.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])=[CH:5][N:6]=1.[CH3:29][NH:30][CH3:31].O1CCCC1>CN(C)C=O>[CH3:29][N:30]([CH3:31])[C:2]1[S:3][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])=[CH:5][N:6]=1
Reactant: O=C1N(Cc2cnc(Cl)s2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CNC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)c1ncc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)s1
Temperature: 120 °C
Yield: 76 %

Procedure:
To a solution of 1′-[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.10 g, 0.24 mmol) in N,N-dimethylformamide (5 mL) was added 2 M dimethyl amine in tetrahydrofuran (2.0 mL, 4.0 mmol) under nitrogen in a sealed tube. The reaction mixture was heated at 120° C. for 16 h. The reaction was quenched with the water, then extracted with ethyl acetate (2×50 mL). The combined organic solution was dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography with 30% ethyl acetate in hexanes to afford 1′-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.08 g, 76%) as a colorless solid: mp 200-202° C.; 1H NMR (300 MHz, CDCl3) δ 7.27 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 7.20 (s, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.08-6.95 (m, 2H), 6.51 (s, 1H), 6.14 (s, 1H), 5.91-5.84 (m, 2H), 5.05 (d, J=15.6 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.84 (d, J=15.6 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 3.06 (s, 6H); 13C NMR (75 MHz, CDCl3) δ177.2, 172.0, 156.1, 149.0, 142.5, 141.5, 139.1, 132.4, 129.1, 124.1, 123.7, 119.7, 119.5, 109.2, 103.3, 101.6, 93.7, 80.5, 58.2, 40.4, 37.2; MS (ES+) m/z 422.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:34]([NH:37][C:38]([C@@H:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41]1)=[O:39])[CH2:35][CH3:36]>O1CCCC1.C(Cl)Cl>[CH2:34]([NH:37][C:38]([C@@H:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]1[C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][CH3:17])=[O:39])[CH2:35][CH3:36]
Reactant: CCCNC(=O)[C@@H]1Cc2ccccc2N1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCNC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](CC)NC(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
0.439 g (1.85 mmol) of N-benzyloxycarbonyl-2(S)-aminobutyric acid prepared as in Example 3 a) is dissolved, under nitrogen, in tetrahydrofuran (50 ml) and the solution is cooled in an ice/water bath. 0.213 g (1.85 mmol) of N-ethylmorpholine is added, followed by 0.253 g (1.85 mmol) of isobutyl chloroformate. After 45 minutes, 0.378 g (1.85 mmol) of the compound obtained in step b) is added and stirring is continued for 12 hours. The suspension is poured into CH2Cl2 (100 ml) and the mixture is washed with 10% citric acid (3×100 ml) and then with 5% NaHCO3 (3×100 ml). After drying and evaporation, a white solid is obtained which crystallizes from CCl4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:32])[C:13]1[CH:18]=[CH:17][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:34]1[N:35]=[C:36]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH3:51])[CH2:46][CH2:45]2)[C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2>C1(C)C(C)=CC=CC=1.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>[CH2:50]([N:47]1[CH2:46][CH2:45][N:44]([C:36]2[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:43]=[C:34]([C:16]3[CH:15]=[CH:14][C:13]([C:12](=[O:32])[NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:18][CH:17]=3)[N:35]=2)[CH2:49][CH2:48]1)[CH3:51]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)NCCOCc2ccccc2)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(C(=O)NCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 22.5 %

Procedure:
N-(2-Benzyloxyethyl)-4-tributylstannylbenzamide (1.23 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.49 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.13 g) in xylene in nitrogen atmosphere for 3 hr. After cooling, the reaction solution was filtered and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol system). The resulting product was dissolved in ethyl acetate and extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-benzyloxyethyl)carbamoyl]phenyl}isoquinoline (0.17 g) as a pale brown viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19](=[O:22])[CH:20]=[CH2:21])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[CH:36]=[C:35]([C:37]2[CH:42]=[C:41]([NH2:43])[CH:40]=[CH:39][N:38]=2)[O:34][N:33]=1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19](=[O:22])[CH2:20][CH2:21][NH:43][C:41]1[CH:40]=[CH:39][N:38]=[C:37]([C:35]2[O:34][N:33]=[C:32]([C:26]3[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])[CH:36]=2)[CH:42]=1)[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: Nc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 89 °C
Yield: 43.7 %

Procedure:
(S)-tert-butyl 4-(tert-butoxycarbonylamino)-5-oxohept-6-enoate (0.94 g) and 2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-amine hydrochloride salt (0.40 g) were dissolved in acetonitrile (4 mL). Diisopropylethylamine (0.52 mL) was added and the mixture wad heated at 89° C. for 25 h. The mixture was cooled to room temperature, diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 0.5:99.5 methanol:dichloromethane then 5:95 methanol:dichloromethane to yield (R)-tert-butyl 4-(tert-butoxycarbonylamino)-7-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-ylamino)-5-oxoheptanoate (316 mg) as a beige foam. 1H NMR (CDCl3): 8.25 (m, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 7.17 (m, 1H), 6.98 (m, 1H), 6.47 (m, 1H), 5.20 (m, 1H), 5.00 (m, 1H), 4.22 (m, 1H), 3.59 (m, 2H), 2.90 (m, 2H), 2.32 (m, 2H), 2.10 (m, 1H), 1.83 (m, 1H), 1.45 ppm (s, 18H). MW=619 confirmed by LC-MS, tr=13.23 min (Method Y) MH+=617-621.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[CH:17]([O-])([O-])OCC>>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]3[N:4]([CH:17]=[N:2][N:1]=3)[CH:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC([O-])[O-]
Reactant: COc1cccc(-c2ccc(NN)nc2)c1
Product: COc1cccc(-c2ccc3nncn3c2)c1

Procedure:
In the manner described in Example 37, a mixture of 2-hydrazino-5-(3-methoxyphenyl)pyridine and ethyl orthoformate provides the product of the Example.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH3:31])=[C:17]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][C@H:23]([C:27]([NH2:29])=[O:28])[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C(F)=C(NC2C3C(=[CH:47][C:48](OC)=[C:49]([O:52][C@H]4CCNC4)C=3)N=CN=2)C=CC=1F>>[C:49]([N:24]1[CH2:25][CH2:26][C@H:21]([O:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:30][CH3:31])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[C:3]=2[F:32])[CH2:22][C@H:23]1[C:27]([NH2:29])=[O:28])(=[O:52])[CH:48]=[CH2:47]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCNC1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCN[C@H](C(N)=O)C1
Product: C=CC(=O)N1CC[C@H](Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2OC)C[C@H]1C(N)=O
Yield: 69 %

Procedure:
The procedure of step (1-7) was repeated except for using the compound obtained in step 4) instead of N-(3-chloro-2,4-difluorophenyl)-7-methoxy-6-((3S)-pyrrolidin-3-yloxy)quinazolin-4-amine to obtain the title compound (10 mg, 69%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]=1[CH2:14][OH:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: CC#N
Product: OCc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 3-phenoxyphenyl methanol (4.0 g, 0.020 mol) in anhydrous acetonitrile was added 1-bromo-2,5-pyrrolidinedione (3.73 g, 0.021 mol) at room temperature. The mixture was stirred at room temperature for one and a half hour under an atmosphere of nitrogen. The solvents were removed under the reduced pressure. Tetrachloromethane (100 mL) was added to the residue, and the mixture was filtered. The filtrate was concentrated into the residue, and the residue was purified by flash chromatography on silica gel using ethyl acetate/n-heptane (1:5) as mobile phase to yield (2-bromo-5-phenoxyphenyl)methanol (4.7 g, 0.017 mol): RP-HPLC (Hypersil C18, 5 μm, 250×4.6 mm; 25%-100% over 10 min with 0.1 M ammonium acetate, 1 mL/min) Rt 11.7 min. TLC (ethyl acetate/heptane 1:5) Rf 0.18.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].[OH:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCON=C(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
n-Butyl iodide (46.9 g.) was added dropwise to a stirred suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), potassium carbonate (52.7 g.) and acetone (200 ml.) under ice-cooling over 5 minutes, and stirred at room temperature for 4 hours. The resultant solution was filtered, and washed with acetone. The filtrate and washing solution were combined together and concentrated in vacuo. After adding water (300 ml.) to the residue, the solution was extracted with methylene chloride three times. The solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-n-butoxyimino-3-oxobutyrate (syn isomer, 48.8 g.), oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29]OS(C)(=O)=O)[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C.[NH4+].[Cl-]>[N:35]([CH2:29][CH2:28][O:27][CH:24]1[CH2:23][CH:12]2[CH2:13][O:14][C:15]3[C:20]([C:11]2([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:26][CH2:25]1)=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])=[N+:36]=[N-:37]
Reactant: CS(=O)(=O)OCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
A solution of methanesulfonic acid 2-[10a-(4-chloro-benzene sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yloxy]-ethyl ester (180 mg, 0.355 mmol) in DMF (5 mL) was treated with NaN3 (46 mg, 0.707 mmol) and the reaction mixture was heated to 80° C. After 16 h, the reaction mixture was cooled to ambient temperature and diluted with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with H2O, saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to afford the title compound (153 mg, 95%): 1H NMR (CDCl3 400 MHz) δ 7.63 (d, J=8.1 Hz, 2H), 7.49 (d, J=7.3 Hz, 2H), 7.07 (m, 1H), 6.42 (m, 1H), 5.25 (dd, J=2.9, 11.7 Hz, 1H), 4.12 (d, J=11.7 Hz), 3.60 (m, 2H), 3.36 (m, 2H), 3.02 (m, 1H), 2.37 (m, 2H), 1.94 (m, 2H), 1.56 (m, 2H), 1.16 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[CH3:19][C:20](=[CH2:22])[CH3:21]>ClCCl>[C:20]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: C=C(C)C
Reactant: O=C(O)c1ccc(Br)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 71 %

Procedure:
A mixture of 4-bromobenzoic acid (100 g, 0.5 mol), trifluoromethane sulphonic acid (2.6 mL, 0.03 mol) and isobutylene (1.5 L) in dichloromethane (1.5 L) was stirred at RT in a closed autoclave for 5 days. The organic layer was washed with an aqueous solution of NaHCO3 (10%), water, brine, dried and concentrated to give tert-butyl-4-bromobenzoate (90 g, 71%).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].B(F)(F)F.[CH3:17]COCC.[N+]([C:27]([O:29][CH2:30][CH3:31])=[O:28])(C([O-])=O)=[N-]>CCOCC>[O:12]=[C:9]1[CH2:10][CH2:11][N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:17][CH2:7][CH:8]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CCOCC
Reactant: CCOC(=O)[N+](=[N-])C(=O)[O-]
Agent: FB(F)F
Product: CCOC(=O)C1CCN(C(=O)OCC)CCC1=O
Temperature: -30 °C

Procedure:
To a cold solution (−30° C.) of 1-carbethoxypiperidin-4-one (3.0 ml, 26.5 mmol) in anhydrous ether, were simultaneously added a solution of boron trifluoride etherate (3.4 ml, 26.5 mmol) in diethyl ether (2.8 ml) and a solution of ethyl diazodicarboxylate (3.6 ml, 34.5 mmol) in diethyl ether (2.8 ml) over 1.5 hours via a syringe-pump. Upon completion of additions, the reaction mixture was allowed to stir for an additional hour at −30° C. and then warmed to room temperature. The reaction mixture was washed with 30% potassium carbonate and the organic phase was dried over Na2SO4 and concentrated in vacuo to give diethyl 5-oxoazepane-1,4-dicarboxylate as a crude yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:36])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[O:34][CH3:35])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:36])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[O:34][CH3:35])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: COc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Yield: 60 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methoxy-phenyl)-acrylonitrile (1.8 g, 5.6 mmol) prepared in Example 58a, AgF (1.7 g, 13 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 24 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 60%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:17]([CH3:19])[CH3:18].O>CN(C=O)C.C(Cl)Cl>[CH:17]([N:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]1)([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nn(C(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.7 %

Procedure:
To a stirred of solution of 3-methyl-4-nitro-1H-pyrazole (0.3 g, 2.4 mmol) in DMF (10 mL) was added potassium carbonate (0.4 g, 2.9 mmol) and 2-iodopropane (0.72 mL, 7.2 mmol). The solution was stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 mL) and extracted into ether (4×30 mL). The combined ethereal extracts were dried (MgSO4) and the solvent removed under vacuum to give a pale yellow oil. Several purifications were performed via column chromatography (SiO2; 200 equiv. 100% DCM) to give 1-isopropyl-3-methyl-4-nitropyrazole (11 mg, 93% isomeric purity). This was combined with another batch (110 mg, purified identically).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:14][CH:13]=3)[N:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: CCOC(=O)c1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 68 %

Procedure:
In substantially the same manner as in Working Example 25, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with ethyl 2-imidazolecarboxylate to give ethyl 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2-imidazolecarboxylate. The yield was 68%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 123-124° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[N:6]([CH2:13][CH3:14])[C:5]2[CH:15]=[N:16][CH:17]=[CH:18][C:4]1=2)[CH3:2].C(N1CCN(C(=O)C)C2C=CN=CC1=2)(=[O:21])C.N1C=CN=C2C=NC=CC=12.CN1CCN(C)C2C=NC=CC1=2>CCOC(C)=O.CCN(CC)CC>[CH2:1]([N:3]1[CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[N:6]([C:13](=[O:21])[CH3:14])[C:5]2[CH:15]=[N:16][CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1c2ccncc2N(CC)C2CCCCC21
Reactant: CC(=O)N1CCN(C(C)=O)c2cnccc21
Agent: CN1CCN(C)c2cnccc21
Agent: c1cc2nccnc2cn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN1c2ccncc2N(C(C)=O)C2CCCCC21

Procedure:
29 (0.250 g, 1.15 mmol) and 10 ml of THF were placed in a 100 ml Schlenk flask. The solution was cooled to −78° C., 0.51 ml of n-BuLi (1.27 mmol, 1.1 eq; 2.5 M in hexane) were added and the reaction solution was stirred without cooling for 30 minutes. After 30 minutes, the reaction solution was cooled back down to −78° C. and 0.09 ml (0.109 g, 1.4 mmol, ρ=1.1051 g/ml) of acetyl chloride were added, the cooling bath was removed and the mixture was stirred without cooling for 1 hour. The reaction was subsequently stopped by means of 4 ml and extracted three times with 20 ml of DCM. The combined organic phases were dried over Na2SO4 and the solvent was distilled off on a rotary evaporator. The crude product was purified on silica gel (EtOAc/MeOH, 10:2) to give 48 mg (0.18 mmol, 16%) of a colorless solid. Rf=0.16 (EtOAc/NEt3, 10:1). 1H NMR: (300 MHz, CDCl3): δ=1.19 (t, 3J=7.2 Hz, 3H, H3C—CH2—N-5), 1.24 (m, 2H), 1.45 (m, 2H), 1.58 (m, 2H), 1.74 (m, 1H), 2.18 (m, 1H), 3.34 (m, 2J=14.4 Hz, 3J=7.2 Hz, 1H, H3C—CHAB—N-5), 3.53 (m, 1H, C—H), 3.57 (m, 2J=15.2 Hz, 3J=7.2 Hz, 1H, H3C—CHAB—N-5), 4.90 (bs, 1H, C—H), 6.62 (d, 3J=5.6 Hz, 1H, H-4), 8.12 (s, 1H, H-1), 8.08 (d, 3J=5.6 Hz, 1H, H-3). 13C NMR (100 MHz, CDCl3): δ=12.4 (H3C—CH2—N-5), 18.9 (C-7), 22.8 (H3C—CO—N-10), 24.7 (C-8), 25.8 (C-6), 28.5 (C-9), 40.0 (H3C—CH2—N-5), 48.7 (C-9a), 53.7 (C-5a), (C-4), 106.4 (C-4), 120.1 (Cq, C-10a), 145.1, 145.2 (C-1, Cq, C-4a), 147.1 (C-3), 167.1 (C═O) ppm. GC-MS (EI): RT 10.39 min, m/e (%) 260 (11), 259 (M+, 100), 230 (8), 218 (9), 217 (79), 216 (40), 203 (4), 202 (23), 203 (3), 202 (23), 201 (4), 189 (6), 188 (31), 187 (4), 186 (3), 174 (11), 162 (4), 161 (6), 160 (5), 158 (4), 148 (5), 146 (6), 136 (3), 132 (4), 131 (12), 120 (6), 43 (3); IR (neat): ν=3398 (s), 2933 (s), 2863 (m), 1731 (m), 1637 (vs), 1595 (vs), 1512 (s), 1546 (w), 1449 (m), 1397 (s), 1365 (s), 1334 (m), 1285 (s), 1239. (m), 1198 (m), 1168 (vs), 1123 (w), 1067 (w), 1068 (w), 1016 (w), 802 (vs), 718 (w), 668 (m). HRMS (EI): calculated for C15H21N3O 259.1685 [M+], found: 259.1687.