Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]([NH2:16])=[O:15].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:16]=[C:14]([CH:13]=[CH:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[F:1])[O:15][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1F
Solvent: Cc1ccccc1
Product: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(CCl)co1
Temperature: 25 °C
Yield: 23 %

Procedure:
4.00 g (17.1 mmol) 3-(2-Fluoro-4-trifluoromethyl-phenyl)-acrylamide, 2.60 g (21.3 mmol) 1,3-dichloroacetone and 40 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a water separator (Dean-Stark trap). After cooling to room temperature, two extractions with 100 ml water were performed, the organic phase was dried over sodium sulphate and the solvent removed in vacuo. Chromatography on silica gel (eluent: n-heptane/ethyl acetate 5:1) gave 1.20 g (23%) 4-chloromethyl-2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazole.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[O:9][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[CH3:17].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>CN(C)C=O>[Si:25]([O:1][C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[O:9][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[CH3:17])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(C)c2c(c(C)c1O)SC(c1ccccc1)O2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(c1ccccc1)O2
Yield: 84 %

Procedure:
2.6 g of 5-hydroxy-4,6,7-trimethyl-2-phenyl-1,3-benzoxathiole, 1.3 g of imidazole and 2.9 g of t-butyldimethylsilyl chloride were dissolved in 20 ml of dimethylformamide, and the mixture was reacted for 24 hours at room temperature. At the end of this time, the reaction mixture was poured into water. The separated product was extracted with benzene, and the extract was washed with a 5% w/v aqueous solution of ammonia and then with water and dried over anhydrous sodium sulfate. The solvent was evaporated off and the product thus obtained was purified by silica gel column chromatography. From the fraction eluted with a 10:1 by volume mixture of cyclohexane and benzene were obtained 3.1 g of the title compound, melting at 95°-98° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[NH:19][CH2:20][CH2:21][S:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C(O[CH:26](O)[C:27]([F:30])([F:29])[F:28])C.[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:20][CH2:21][S:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(O)C(F)(F)F
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)SCCN3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)SCCN3CC(F)(F)F
Yield: 55.9 %

Procedure:
This compound was prepared according to General Method 7 (EXAMPLE 5) from 2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline (11 mg, 0.034 mmol), trifluoroacetaldehyde ethyl hemiacetal (49 mg, 0.34 mmol) and NaBH3CN (14 mg, 0.22 mmol) in 0.7 mL TFA to afford 7.8 mg (56%) of 2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline, a yellow oil, after flash chromatography (9:1 hexanes:EtOAc). Data for 2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline: 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.21 (broad s, 1H), 7.03 (s, 1H), 5.46 (hept, 1H, J=6.1), 3.97 (q, 2H, J=8.8), 3.77-3.83 (m, 2H), 3.08-3.14 (m, 2H), 1.38 (d, 6H, J=6.1).
Reaction SMILES: [C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>>[C:4]([O:6][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])(=[O:5])[CH2:3][CH2:2][C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)=[O:7]
Reactant: CCCCCCCCCCCCBr
Reactant: CC1(C)CC(OC(=O)CCC(=O)[O-])CC(C)(C)N1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)CCC(=O)OC1CC(C)(C)NC(C)(C)C1

Procedure:
The product is prepared as described in Example 4b by reacting 30.9 g (0.12 mol) of mono(2,2,6,6-tetramethyl-4-piperidyl) succinate with 29.9 g (0.12 mol) of 1-bromododecane in the presence of 12.1 g (0.12 mol) of triethylamine. The product obtained has a boiling point of 195° C./5.3 mbar.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH:15]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16]1>>[CH:15]1([N:18]2[CH2:23][CH2:22][N:21]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: C1CN(C2CC2)CCN1
Agent: Cl
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CC2)CC1

Procedure:
This example was prepared according to Example 4 employing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-cyclopropylpiperazine dihydrochloride, which was prepared according to Gillaspy, et. al. Tetrahedron Lett. 1995, 36 (41), 7399-7402. m/z (ES+) M+1=271.2; HPLC tR=1.43 min. 1H NMR (500 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 7.19 (d, J=7.3 Hz, 1H), 7.11 (d, J=7.0 Hz, 2H), 3.69-3.50 (m, 4H), 2.59 (t, J=5.2 Hz, 4H), 2.48 (ddd, J=8.9, 6.3, 4.3 Hz, 1H), 1.96 (ddd, J=8.2, 5.5, 4.3 Hz, 1H), 1.68-1.59 (m, 2H), 1.26 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 0.49-0.44 (m, 2H), 0.44-0.38 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[O:5][CH2:6][CH2:7][NH2:8].[CH3:16][C:17]1C=CC(S(OCCC)(=O)=O)=C[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[O:5][CH2:6][CH2:7][NH:8][CH2:16][CH2:17][CH3:18]
Reactant: CS(=O)(=O)c1cc(F)cc(OCCN)c1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNCCOc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 120 °C
Yield: 43.2 %

Procedure:
2-[3-Fluoro-5-(methylsulfonyl)phenoxy]ethanamine (0.3 g, 1.26 mmol), propyl 4-methylbenzenesulfonate D2 (1.04 ml, 12.76 mmol) and potassium carbonate (0.35 g, 2.52 mmol) in acetonitrile (10 ml). The mixture was heated under microwave radiation at 120° C. for 45 min. The reaction mixtures were cooled to room temperature, filtrated and pooled before the volatiles were evaporated. Purification by flash column chromatography (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.15 g, 44%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether. MS m/z (relative intensity, 70 eV) 277 (M+, 2), 248 (26), 138 (3), 94 (3), 74 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]Cl)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:22]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][N:38]3[CH2:39][CH2:40][N:35]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36][CH2:37]3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=c1sc2cc(Cl)ccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1sc2cc(Cl)ccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 61.7 %

Procedure:
A solution of compound (X) (3.71 g, 20 mmol), K2CO3 (3.31 g, 24 mmol), 4-benzhydrylpiperazine (XId) (6.06 g, 24 mmol), and KI (3.98 g, 24 mmol) in DMF (20 ml) was stirred at 100° C. for 5 hours, concentrated in vacuo and extracted with dichloromethane. The resulting dichloromethane layer was dried over MgSO4, and subjected to column chromatography on silica gel. The eluate eluted with dichloromethane/ethyl acetate (10/1) was recrystallized from ether to obtain compound (XIId) (5.9 g, yield=61.7% ) as colorless prism-shaped crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([OH:19])=[C:13]([CH3:20])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:1])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1oc2c(C)c(C)c(O)c(C)c2c1-c1ccccc1
Product: COc1ccc(C(=O)Oc2c(C)c(C)c3oc(C)c(-c4ccccc4)c3c2C)cc1
Yield: 64 %

Procedure:
Using 2,4,6,7-tetramethyl-3-phenylbenzofuran-5-ol and 4-methoxybenzoyl chloride, the title compound was obtained in the same manner as in Example 26.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1.[C:18](=O)([O:21]C)[O:19][CH3:20]>C1COCC1>[CH3:9][O:10][C:11]1[N:12]=[C:13]([CH2:17][C:18]([O:19][CH3:20])=[O:21])[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(C)n1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(OC)n1
Reaction time: 2 h

Procedure:
To the solution of LDA (18.3 mL, 36.5 mmol) in THF (120 mL) cooled to −78° C. was added 2-methoxy-6-methylpyridine (1.5 g, 12.2 mmol) in THF (15 mL) dropwise, and then the mixture was stirred at −78 degree for 2 h. Dimethyl carbonate (1.2 mL, 14.6 mmol) was added quickly and continued to stir at −78° C. for 15 min. The reaction was quenched by H2O at −78° C. The solution was extracted with ethyl acetate, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified with a standard method to give desired compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].CC1(C)C(C)(C)OB([C:50]2[CH:51]=[C:52]([OH:56])[CH:53]=[CH:54][CH:55]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:50]6[CH:55]=[CH:54][CH:53]=[C:52]([OH:56])[CH:51]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6cccc(O)c6)c5)nn34)c(Cl)c21
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
A mixture of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (120 mg, 0.188 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61.9 mg, 0.281 mmol) and 2M Na2CO3 (0.188 mL, 0.375 mmol) in DMF (2 mL) was degassed for 15 min by bubbling N2 through the reaction mixture. Then, tetrakis(triphenylphosphine)pallafium(0) (15.17 mg, 0.013 mmol) was added and the degassing was continue for another 5 min. The mixture was then heated at 90° C. for 16 h. After cooling to room temperature, water was added and the mixture was extracted with ether (2×50 mL), washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by biotage (10-40% EtOAc/hexane) to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.138 mmol, 73.5% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.02 (t, J=1.6 Hz, 1H), 7.82 (dt, J=7.6, 1.4 Hz, 1H), 7.54-7.51 (m, 1H), 7.47-7.43 (m, 1H), 7.33-7.29 (m, 1H), 7.19-7.13 (m, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.02-7.00 (m, 1H), 6.98 (s, 2H), 6.93 (s, 1H), 6.81 (ddd, J=8.0, 2.5, 0.9 Hz, 1H), 6.42 (dd, J=8.1, 2.3 Hz, 2H), 6.39-6.35 (m, 1H), 6.10-5.98 (m, 1H), 5.40-5.30 (m, 2H), 5.07 (s, 1H), 4.29-4.18 (m, 2H), 3.67 (s, 3H), 3.18 (t, J=4.4 Hz, 2H), 2.87 (s, 3H), 1.18 (s, 9H). LCMS (M+H)=653.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1.[CH3:24][O-:25].[Na+]>C1COCC1>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=[C:2]([O:25][CH3:24])[CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: C[O-]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c([N+](=O)[O-])cn1
Reaction time: 0.02 h

Procedure:
To an ice-bath cooled suspension of cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (400 mg, 1.174 mmol) in THF (2.3 mL) was added sodium methoxide (25 wt. % in MeOH (0.859 mL, 3.76 mmol)). The mixture was stirred in an ice bath for 1 minute. The ice bath was removed and the reaction was stirred for 30 minutes. The mixture was diluted with 10% IPA/DCM (5 mL) and washed with saturated aqueous NaHCO3 (1 mL). The layers were separated, and the organic layer was dried with Na2SO4 and the mixture purified via flash chromatography using a linear gradient of 0% to 5% of 1% NH4OH in MeOH in DCM. The title compound was collected as a yellow solid (289 mg, 73%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[C:3]=1[F:17].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:3]1[C:4]([F:16])=[CH:5][C:6]2[CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][N:9]3[C:10]=2[C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1NCCn2c1cc1cc(F)c(F)c(Br)c12
Product: O=C1NCCn2c1cc1cc(F)c(F)c(-c3ccc(F)cc3)c12

Procedure:
The title compound, off-white solid (69 mg, 87%), MS (ISP) m/z=317.0 [(M+H)+], mp 286.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-7,8-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 6) (75.3 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=1)=[O:16]
Reactant: CCCCCC(=O)Nc1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: CCCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 86 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]hexanamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 87 mg of the title compound (86%) as a yellow powder in 98.5% purity by HPLC (Rt: 4.71, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[CH:7][C:3]=1[NH:4][CH2:5][CH3:6].[OH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21]>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[N:4]([NH:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][OH:15])[CH2:5][CH3:6]
Reactant: CCNc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: NCCOCCO
Product: CCN(NCCOCCO)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
0.01 mole (2.35 g) of 2,5-dichloro-4-nitro-N-ethylaniline is heated in 10 ml of β-(β'-hydroxyethoxy)ethylamine for 30 minutes on a steam bath.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: COc1cccc(C=O)c1
Solvent: CCO
Solvent: O
Product: COc1cccc(C2CC(=O)c3cc(Br)ccc3O2)c1
Yield: 35.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (18 g, 84.1 mmol), 3-methoxy-benzaldehyde (11.4 g, 84.1 mmol) and borax (32 g, 84.1 mmol) in ethanol (112 mL) and H2O (187 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-methoxyphenyl)chroman-4-one (10 g, 36%). 1H-NMR (CDCl3): 2.71 (d, 1H), 2.99 (t, 1H), 3.75 (s, 3H), 5.38 (d, 1H), 6.90 (m, 4H), 7.27 (t, 1H), 7.51 (d, 1H), 7.95 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([Cl:8])=[CH:6][CH:7]=1)(=[O:15])[CH3:14]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 98.5 %

Procedure:
A solution of 3-amino-6-chlorobenzotrifluoride (1.045 g, 5.34 mmol, Aldrich) in acetic anhydride (5 mL) was stirred at room temperature for 12 h to produce a white needle precipitate. It was filtered to give 1.250 g (98.5%) of 3-acetamido-6-chlorobenzotrifluoride. 1H NMR (CDCl3): δ2.193 (s, 3H); 7.420 (d, 1H, J=8.7 Hz); 7.726 (m, 2H), 7.804 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(C2CCCN2)cc1
Product: COc1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound, white solid, m.p. 133° C. and MS: m/e=352 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-methoxy-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: CC(O)=O.[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[CH2:8][O:9][C:10]1[C:11]([N+:16]([O-])=O)=[N:12][CH:13]=[CH:14][CH:15]=1>[Fe].CCO>[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[CH2:8][O:9][C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ncccc1OCc1c(Cl)cccc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ncccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred mixture of AcOH (650 mL) and EtOH (500 mL) was suspended 3-(2,6-dichloro-benzyloxy)-2-nitro-pyridine (37.4 g, 0.11 mol) and iron chips (69.4 g, 0.11 mol). The reaction was heated slowly to reflux and allowed to stir for 1 hr. The reaction was cooled to room temperature then filtered through a pad of celite. The resulting filtrate was neutralized with conc. NH4OH (600 mL) and then extracted with EtOAc (3×500 mL). The combined organic extracts were washed with saturated NaHCO3 (2×100 mL), H2O (2×100 mL) and brine (1×100 mL) then dried (Na2SO4), filtered and concentrated to dryness under vacuum to yield 3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (32.4 g, 0.11 mol, 99%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.56 (m, 3H), 7.46 (dd, 2H), 7.36 (d, 1H), 6.62 (dd, 1H), 6.18 (br s, 2H, NH2), 5.24 (s, 2H); MS m/z 270 [M+1].
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[OH:9][C:10]1[N:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>CN(C)C=O>[OH:9][C:10]1[N:17]=[CH:16][C:15]([I:1])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1cccnc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: N#Cc1cc(I)cnc1O
Temperature: 60 °C
Yield: 188 %

Procedure:
9 g (0.5 eq) of N-iodosuccinimide at room temperature is added to a solution of 10 g (83 mmol) of 2-hydroxynicotinonitrile in 150 ml of anhydrous dimethylformamide. The reaction mixture is stirred at 60° C. After 30 minutes of stirring, 9 g (0.5 eq) of N-iodosuccinimide is added and then the reaction mixture is stirred at 60° C. for 5 hours. The solvent is evaporated and the precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 18.5 g (90%) of 2-hydroxy-5-iodonicotinonitrile in the form of a beige powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added butyryl chloride (19.6 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (46.2 mg, 73%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([Cl:13])=[CH:11][NH:10][CH:9]=1.[C:14](N1C=CN=C1)(=[O:16])[CH3:15]>CCOCC>[C:14]([N:10]1[CH:11]=[C:12]([Cl:13])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9]1)(=[O:16])[CH3:15]
Reactant: CC(=O)n1ccnc1
Reactant: Clc1ccccc1-c1c[nH]cc1Cl
Solvent: CCOCC
Product: CC(=O)n1cc(Cl)c(-c2ccccc2Cl)c1
Yield: 48 %

Procedure:
The mixture of 4.35 g of 3-(2-chlorophenyl)-4-chloropyrol and 5.3 g of N-acetylimidazole was heated for 4 hours at 100° to 110° C. After cooling, the reaction mixture was dissolved in 200 ml of ether and the resulting ether solution was washed with successive, diluted hydrochloric acid and water. The ether solution was dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residual crude product was purified by silicagel chromatography using mixed solvent of n-hexane and benzene (1:1) to obtain 2.5 g of the desired product (colorless crystal, m.p. 82°-84° C.).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH2:18]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=1)(=[O:31])=[O:30])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCCc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1
Yield: 25 %

Procedure:
According to the method described in example S20a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol) was reacted with 4-pentylbenzene-1-sulfonyl chloride to yield the title compound as a white solid (9 mg, 25%). MS ESI 447.3 [M+H]+, calcd for [C24H34N2O4S+H]+ 447.22