Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Si]([O:13][C@@H:14]([CH3:39])[C@@H:15]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[C:31]([Cl:37])[C:30]=1[CH3:38])[C:16]([NH:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)(C(C)(C)C)(C)C>C1C=CC=CC=1>[Cl:37][C:31]1[C:30]([CH3:38])=[C:29]([NH:28][C@@H:15]([C:16]2[O:27][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][N:18]=2)[C@@H:14]([OH:13])[CH3:39])[CH:34]=[CH:33][C:32]=1[C:35]#[N:36]
Reactant: Cc1c(N[C@@H](C(=O)NCC(=O)c2ccccc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1c(N[C@@H](c2ncc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Yield: 3.6 %

Procedure:
A 100 mL, round bottomed flask was charged with phosphorous oxychloride (0.5 mL, 5.24 mmol) and benzene (20 mL). (2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-N-(2-oxo-2-phenylethyl)butanamide (1.14 g, 2.28 mmol) was then added to the mixture which was then placed under reflux for 4 h. The mixture was then concentrated en vacuo, then partitioned between EtOAc (40 mL) and a saturated solution of sodium bicarbonate (30 mL). The organic layer was washed with water (20 mL), dried (Na2SO4). Purification by flash column chromatography [hexanes/Et2O (3:2) as eluent] afforded the title compound as a white solid (30 mg, 4% yield). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.59 (d, J=8 Hz, 2H), 7.32-7.42 (m, 4H), 7.28 (s, 1H), 6.58 (d, J=8 Hz, 1H), 5.17 (d, J=7 Hz, 1H), 4.93-4.95 (m, 1H), 4.66-4.75 (m, 1H), 2.40 (s, 3H) and 1.63 (d, J=6 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([S:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32]I>>[Cl:17][C:18]1[CH:23]=[C:22]([S:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=2[CH:10]=1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Reactant: FC(F)(F)Sc1ccc(OCCCI)c(Cl)c1
Product: CCC1(C(=O)O)Cc2cc(OCCCOc3ccc(SC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4 employing the phenol prepared in Example 4, Step 1 and the iodide prepared in Step 2.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>O1CCOCC1.O.CCOC(C)=O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:21]=[CH:20][N:19]=[C:18]5[C:13]=4[C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16](=[O:22])[NH:17]5)=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:36])=[CH:30][CH:29]=1
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Yield: 73 %

Procedure:
Compound 218 (50 mg, 0.14 mmol), 1-chloro-4-isocyanato-benzene (33 mg, 0.22 mmol), and DIEA (0.07 mL, 0.43 mmol) were dissolved in dioxane (2 mL) and stirred and stirred for 30 minutes at 100° C. in microwave. The reaction mixture was diluted with H2O/EtOAc. The resulting precipitate was filtered, washed with EtOAc, and dried under vacuum to provide 220 (51 mg, 71% yield) as a tan solid. LC-MS (M+H=499, obsd.=499).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A mixture of 4-cyanophenol (5.0 g, 42 mmol), benzylbromide (8.6 g, 50 mmol), potassium carbonate (11.6 g, 84.0 mmol) in DMF (40 mL) was stirred at 100° C. for 3 h. The precipitate was filtered off and the filtrate was diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4) and concentrated. The resulting crude product was purified by silica gel column chromatography (eluting with petroleum ether/EtOAc from 20/1 to 5/1) to give 4-(benzyloxy)benzonitrile as a white solid (8.1 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[C:11]([CH3:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.NN>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1onc(-c2ccc(F)cc2)c1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione (5.9 g, 18 mmol) in THF (248 mL) and ethanol (21 mL) at 0° C. was added hydrazine hydrate (6.7 g, 6.5 mL, 134 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then filtered and the filtrate diluted with HCl (1 N) and extracted with ethyl acetate. The combined organic extracts were then washed with HCl (1 N) and the aqueous layer made basic with NaOH (6 N). The aqueous layers were extracted with ethyl acetate and the combined organic layers washed with brine and dried over sodium sulfate. Concentration afforded the title compound (2.0 g, 54%) as a light yellow oil. MS: m/e=190.3 [M+H]+.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:8]([C:32]2[O:36][N:35]=[CH:34][CH:33]=2)[CH:7]=1.Cl.O>C(O)C>[Cl:5][C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:8]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1-c1ccno1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a stirred mixture of sodium ethoxide (0.14 g, 1.0 mmol) in ethanol (2 mL) was added 2-(4-chloro-2-isoxazol-5-yl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.465 g, 1.0 mmol) in ethanol (3 mL). The resulting mixture was stirred at ambient temperature for 3 hours. To the reaction was then added 3M hydrochloric acid (2 mL) and the resulting solution was poured into water (30 mL). This was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel gave the title compound (0.34 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)[N:6]=1)=[O:4].Br[C:18]1[CH:19]=[N:20][CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)=[N:9][CH:8]=[C:7]([CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(C2CCOC2)cnc1N
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1nc(C2CCOC2)cnc1Nc1cncnc1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 3-amino-6-(tetrahydrofuran-3-yl)pyrazine-2-carboxylic acid methyl ester (300 mg, 1.34 mmol), 5-bromopyrimidine (299 mg, 1.88 mmol) and potassium carbonate (334 mg, 2.42 mmol) in xylene (15 ml) and water (51 μl, 2.82 mmol) was evacuated and vented with argon. Palladium (II) acetate (12.1 mg, 54 μmol) and xantphos (23.3 mg, 40 μmol) were added and the reaction mixture was stirred at 140° C. for 16 hr. The reaction mixture was cooled to r.t., poured into 50 ml ethyl acetate and extracted with water. The organic phase was washed with brine and the aqueous layers were back-extracted with ethyl acetate. The organic layers were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light solid (211 mg, 52%).
Reaction SMILES: [N:1]1([C:6]2[CH:22]=[CH:21][C:9]([CH2:10][CH:11]3[C:16](=[O:17])[O:15]C(C)(C)[O:13][C:12]3=[O:20])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1>O.FC(F)(F)C(O)=O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([C:12]([OH:20])=[O:13])[C:16]([OH:17])=[O:15])=[CH:21][CH:22]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC1(C)OC(=O)C(Cc2ccc(-n3cncn3)cc2)C(=O)O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(Cc1ccc(-n2cncn2)cc1)C(=O)O
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
5-(4-(1H-1,2,4-triazol-1-yl)benzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.0 g, 33.2 mmol, Intermediate 45, step b) was dissolved in a mixture of water (30 mL) and trifluoroacetic acid (50 mL). The mixture was heated to 65° C. After 2.5 hours, the mixture was allowed to cool to 23° C. Water and trifluoroacetic acid were removed by rotary evaporation at 45° C. Toluene (100 mL) was added to the residue then the mixture was concentrated by rotary evaporation at 45° C. Tetrahydrofuran (100 mL) and 6 M aqueous hydrochloric acid solution (28 mL) was added to the residue in sequence. The resulting heterogeneous mixture was stirred at 23° C. After 10 minutes, the mixture was concentrated by rotary evaporation at 45° C. Tetrahydrofuran (100 mL) was added to the residue and the mixture concentrated by rotary evaporation at 45° C. Toluene (100 mL) was added to the residue and the mixture concentrated by rotary evaporation at 45° C. The resulting white solid was dried under vacuum at 40° C. The solid product was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[C:17]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>O1CCOCC1>[C:17]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]([S:23]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
This compound was prepared from trans-2-amino-1-cyclohexanecarboxylic acid (1.0 g, 7.0 mmol) by reacting it with sodium carbonate (1.48 g, 14.0 mmol) and biphenyl-4-sulfonyl chloride (2.02 g, 8.0 mmol) in dioxane:water (70:35 mL) in the same manner as described in Example 1. The yield was 1.48 g (59%), the melting point was 220-222° C., and mass spectrometry revealed a molecular ion peak (MH)+ at m/z 360.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[I:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CS(O[CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])(=O)=O>C1C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[CH2:20]([O:19][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([I:27])=[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:39][CH2:38][CH2:37][CH:36]=[CH2:35])[CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=CCCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccccc2c1I
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CCCCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccccc2c1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
A solution of 80 (1.00 g, 2.11 mmol, 1 equiv) in benzene (100 mL) was treated with 50% w/v aqueous NaOH (20 mL). Benzyltributylammonium chloride (1.32 g, 4.22 mmol, 2 equiv) was added followed by 5-[(methanesulfonyl) oxy]-1-pentene (1.73 g, 10.53 mmol, 5 equiv). The resulting biphasic mixture was stirred vigorously at 25° C. for 12 h. The layers were allowed to separate and the aqueous portion was extracted with EtOAc (2×30 mL). The combined organic portions were washed with H2O (2×100 mL) and saturated aqueous NaCl (50 mL). Drying (MgSO4), filtration, and concentration was followed by flash chromatography (SiO2, 3.5×14 cm, 5% EtOAc-hexane) to furnish 81 (0.975 g, 1.15 g theoretical, 85%) as a pale yellow solid: mp 69-71° C.; 1H NMR (500 MHz, CDCl3) major rotamer δ 8.34-8.32 (m, 1H), 8.23-8.21 (m, 1H), 7.62-7.49 (m, 4H), 7.42-733 (m, 3H), 6.70 (s, 1H), 5.81-5.71 (m, 1H), 5.34-5.18 (m, 2H), 5.01-4.93 (m, 2H), 3.84 (ddd, J=17.5, 12.6, 7.6 Hz, 1H), 3.37-3.31 (m, 1H), 2.07-2.02 (m, 2H), 1.74-1.65 (m, 2H), 1.31 (s, 9H); 13C NMR (125 MHz, CDCl3) major rotamer δ 155.1, 154.0, 143.2, 137.9, 136.4, 135.4, 132.8, 128.7 (2C), 128.5, 128.2 (2C), 127.2, 126.2, 122.5, 115.0, 107.8, 95.1, 80.1, 70.3, 49.1, 31.3, 28.6, 28.3 (3C), 27.5; IR (film) νmax 3067, 3036, 2974, 2923, 1697, 1615, 1590 cm−1; FABHRMS (NBA-NaI) m/z 544.1337 (M+Na+, C27H30INO3 requires 544.1349).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(O)c1ccc(Br)cn1
Reactant: C#Cc1ccccc1
Product: CC(O)c1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, brown solid, MS: m/e=224.2 (M+H+), can be prepared in accordance with the general method of example 31, step 1 from rac-1-(5-bromopyridin-2-yl)ethanol and phenylacetylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].Cl.[CH3:30][N:31](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN>ClCCl.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:31][CH3:30])=[O:9]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 3-[2,3-Dimethoxy-6-(1-oxo-indan-4-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 199) (30 mg, 0.078 mmol) in dichloromethane, were added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (22 mg, 0.117 mmol), 1-Hydroxybenzotriazole hydrate (HOBT) (23 mg, 0.156 mmol) and triethylamine (0.1 mL, 0.234 mmolo) and 1M methylamine solution (0.15 mL, 0.156 mmol) and the resultant reaction mixture was stirred at 16 h at RT. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-60% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)(O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(O)c1cccc(Cl)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-(3-chloro-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one (from Example 5a supra) was suspended in a mixture of triethylsilane (5 mL, 31.3 mmol) (Aldrich) and trifluoroacetic acid (12.5 mL) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate (100 mL) and treated with solid sodium carbonate (10.5 g). After stirring for 30 minutes, mixture was extracted with water (2×100 mL) and brine (100 mL). Aqueous layers were back washed with ethyl acetate (100 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40M, dichloromethane then 7.5% ethyl acetate in dichloromethane as solvent). Fractions containing product were combined, concentrated and recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 2.03 g, 73.0% over two steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:11]=[CH:12][CH:13]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][NH2:17])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc(/C=C/c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)c1
Solvent: CO
Product: COc1cccc(/C=C/c2cccc(CCCN)c2)c1

Procedure:
(E)-2-(3-(3-(3-Methoxystyryl)phenyl)propyl)isoindoline-1,3-dione was deprotected following the method used in Example 90 except that the reaction mixture was stirred overnight in methanol. Purification by preparative thin layer chromatography on silica gel gave Example 97. Yield (0.010 g, 16%): 1H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.25-7.29 (m, 2H), 7.21 (d, J=4.0 Hz, 2H), 7.15-7.16 (m, 2H), 7.09 (d, J=7.2 Hz, 1H), 6.82-6.83 (m, 1H), 3.77 (s, 3H), 2.53-2.63 (m, 4H), 1.65-1.72 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]2[N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:16][C:17]([CH3:25])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[NH2:18]>>[CH3:15][C:2]1([CH3:1])[CH2:11][C:10]2[N:9]=[C:8]([C:12]([NH:18][C:17]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)([CH3:25])[CH3:16])=[O:14])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: CC1(C)CCc2ccc(C(=O)O)nc2C1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc3c(n2)CC(C)(C)CC3)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 7,7-dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid (Example 143 d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, LC-MS (UV peak area/EIC) 100%, 329.1977 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CN(C)CCCN
Product: CN(C)CCCNC(=O)CN1CCCC1=O

Procedure:
From 12.8 g. of ethyl 2-oxo-1-pyrrolidineacetate and 15.3 g. of 3-(dimethylamino)propylamine (U.S. Pat. No. 2,459,080), following the procedure of Example 1, there is obtained N-[3-(dimethylamino)propyl]-2-oxo-1-pyrrolidineacetamide; b.p. 157°-159° C./0.15 mm.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=3)([CH2:13][CH2:14]1)[O:11][CH2:10]2>N1C=CC=CC=1.CCOC(C)=O.[Zn]>[O:23]([C:19]1[CH:18]=[C:17]([C:12]23[CH2:15][CH2:16][C:9]([CH2:8][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([CH2:14][CH2:13]2)[CH2:10][O:11]3)[CH:22]=[CH:21][CH:20]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC(=O)OC
Reactant: ICC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 50 °C
Yield: 70.2 %

Procedure:
A mixture of Zn (622 mg, 9.52 mmol), anhydrous pyridine (5 mL) and methyl acrylate (0.95 mL, 9.52 mmol) was warmed to 50° C., after which NiCl2.6H2O (283 mg, 1.19 mmol) was added. The resulting mixture was heated to 65° C. for 1 h and stirred until the color of the solution became reddish-brown, then was cooled to 0° C., after which a solution of 4-(iodomethyl)-1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octane (500 mg, 1.190 mmol) in pyridine (2 mL) was added. The reaction mixture was allowed to warm to rt overnight, then was diluted with EtOAc (10 mL) and the resulting mixture was filtered off through a pad of CELITE®. The filtrate was washed with 1 N aq. HCl and brine, dried (MgSO4), and concentrated in vacuo. The residual crude oil was purified by flash chromatography (SiO2; gradient from 0 to 50% EtOAc:hexanes) to afford the title compound as a colorless oil (318 mg, 73% yield). LCMS, [M+H]+=381, 1H NMR (400M Hz, CDCl3) δ 7.39-7.24 (m, 3H), 7.19-7.06 (m, 3H), 7.04-6.98 (m, 2H), 6.86 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 3.82 (s, 2H), 3.70 (s, 3H), 2.31 (t, J=7.3 Hz, 2H), 2.10-1.98 (m, 4H), 1.76-1.57 (m, 6H), 1.22-1.12 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][C:26]1[O:30][N:29]=[CH:28][C:27]=1[S:31](Cl)(=[O:33])=[O:32]>CN(C=O)C>[CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[N:12]([S:31]([C:27]1[CH:28]=[N:29][O:30][C:26]=1[CH3:25])(=[O:33])=[O:32])[CH:11]=[CH:10]3
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Reactant: Cc1oncc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oncc1S(=O)(=O)n1ccc2c3c(ccc21)OCCN(C(=O)OC(C)(C)C)C3C
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 5-methyl-4-isoxazolesulfonyl chloride (21 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 1-methyl-8-[(5-methylisoxazol-4-yl)sulfonyl]-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (0.010 g) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (1 mg). MS m/z 348 [M+H]+.