Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C2C(=CC=1)C=C([C@@H](C)C([O:16][C@H:17]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=1[Cl:26])=O)C=C2.C1(C)C=CC=CC=1.CC(C)([O-])C.[K+]>CO.O>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[CH2:18][C@@H:17]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[OH:16]
Reactant: COc1ccc2cc([C@@H](C)C(=O)O[C@@H](Cc3c(Cl)cncc3Cl)c3ccc(OC)c(OC)c3)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc([C@@H](O)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(R)—((S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) 2-(6-methoxynaphthalen-2-yl)propanoate (30 g, 56 mmol) was dissolved in MeOH, and toluene was slowly added. Potassium terbutoxide was slowly added to the suspension. The mixture was stirred for 24 hours at RT. The reaction was diluted with water (500 ml), and the aqueous mixture was extracted with CHCl3 (500 ml). The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuum. The residue was crystallized from CHCl3 (100 ml) and hexane (20 ml). The mother liquor was concentrated and recrystallized with an analogous procedure giving a second crop of desired compound. In total, 16 g of the title compound (87% yield) were obtained. Chiral HPLC analysis Rt=58.03 min; eluent:hexane:isopropanol=95:5; [α]D20=+10.21 (c=0.506, Methanol); 1H NMR (400 MHz, acetone) δ ppm 8.47 (s, 2H), 6.96-7.15 (m, 1H), 6.87 (m, 2H), 4.93-5.21 (m, 1H), 4.50 (d, J=3.97 Hz, 1H), 3.78 (s, 6H), 3.44 (dd, J=12.79, 8.38 Hz, 1H), 3.22 (dd, J=13.01, 5.51 Hz, 1H). MS/ESI+ [MH]+: 328.19
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:19][C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:17][CH:16]([CH3:18])[CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[O:31])=[CH:13][CH:12]=1)[NH:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:30]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cnc3c(C)cccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc2cc(NC(CC(C)C)c3ccc(C(=O)NCCC(=O)O)cc3)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 3-{4-[3-Methyl-1-(8-methyl-quinolin-3-ylamino)-butyl]-benzoylamino}-propionic acid methyl ester (44 mg, 0.1 mM) in 1:1 mixture of THF/MeOH (1 mL) was added 1N NaOH solution (0.25 mL, 0.25 mM). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated to remove organic solvent. The aqueous solution was diluted with DCM (5 mL), acidified by 1N HCl solution to pH=3-4. The organic solution was separated and the aqueous solution was extracted with 10% i-PrOH-DCM (3×5 mL). The combined organic solution were dried (Na2SO4) and concentrated to give a yellow solid product (˜100%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.59 Hz, 3H) 0.98 (d, J=6.34 Hz, 3H) 1.56 (dt, J=13.30, 6.77 Hz, 1H) 1.71 (dt, J=13.36, 6.62 Hz, 1H) 1.76-1.85 (m, 1H) 2.46 (t, J=7.07 Hz, 2H) 2.59 (s, 3H) 3.36-3.46 (m, 2H) 4.64 (t, J=7.07 Hz, 1H) 7.10 (br. s., 1H) 7.21 (br. s., 1H) 7.26 (d, J=6.83 Hz, 1H) 7.32 (t, J=7.56 Hz, 1H) 7.45 (d, J=8.05 Hz, 1H) 7.53 (d, J=8.05 Hz, 2H) 7.76 (d, J=8.29 Hz, 2H) 8.42 (t, J=5.49 Hz, 1H) 8.60 (d, J=2.44 Hz, 1H), one proton was exchanged. LC-MS: 420.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([OH:35])=O)[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]([F:48])([F:47])[C:39]([O:42][S:43](=[O:46])(=[O:45])[NH2:44])([CH3:41])[CH3:40]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([NH:44][S:43]([O:42][C:39]([CH3:41])([CH3:40])[C:38]([F:37])([F:48])[F:47])(=[O:45])=[O:46])=[O:35])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(OS(N)(=O)=O)C(F)(F)F
Product: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC(C)(C)C(F)(F)F

Procedure:
2-[2-Ethyl-1-(2,2,2-trifluoro-1,1-dimethyl-ethoxysulfonylaminocarbonyl)-cyclopropylcarbamoyl]-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared according to the method presented in Example 27. Treatment of 2-(1-carboxy-2-ethyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.01 mmol) occurred under the same conditions, adjusted for scale with the exception of utilizing sulfamic acid 2,2,2-trifluoro-1,1-dimethyl-ethyl ester to afford acylsulfamate (450 mg, 65%): LCMS found 688.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([S:17][CH2:18][CH2:19][CH2:20]N(C)C)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=[O:31])=CC=1.CNC>N1C=CC=CC=1>[CH2:1]([N:8]1[C:16]([S:17][CH2:18][CH2:19][CH2:20][OH:31])=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)CCCSc1c2ccccc2nn1Cc1ccccc1
Agent: CNC
Solvent: c1ccncc1
Product: OCCCSc1c2ccccc2nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The resulting oil (7.3 g--yield: 61%), which tends to decompose if distillation thereof is attempted, shows by elemental analysis and under NMR spectrum to consist of practically pure 2-benzyl-3-(3-hydroxypropylthio)-indazole. (b) To a solution of 3 g (0.01 mols) of the preceding product in 15 ml of pyridine there is added 1.9 g (0.01 mols) of p-toluenesulfonylchloride. The mixture is left for 3 hours under stirring at room temperature, is then poured into 100 ml of a water-ice mixture and the oil which separates is extracted with ethyl ether. The oil which is obtained by removing the solvent is dissolved in 20 ml of a toluene solution containing 10% (0.044 mols) of dimethylamine and the resulting solution is heated for 16 hours at 120° in a closed test tube. At the end of the heating cycle, the toluene solution is extracted with an equal volume of 2 N HCl and made basic with NaOH. The oil which separates is extracted with ether and to the ether solution there is added gaseous HCl. The hydrochloride which precipitates is removed by filtration and recrystallized from isopropanol-isopropyl ether.
Reaction SMILES: I[CH:2]([CH3:8])[CH2:3][C:4]([F:7])([F:6])[F:5].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[F:5][C:4]([F:7])([F:6])[CH2:3][CH:2]([S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: Sc1ccccc1
Reactant: CC(I)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(CC(F)(F)F)Sc1ccccc1
Yield: 79 %

Procedure:
To a solution of 54.9 mmol 3-iodo-1,1,1-trifluorobutane in 50 ml N,N-dimethylformamide were added 49.9 mmol thiophenol and 74.9 mmol potassium carbonate. The mixture was ultrasonicated at room temperature for 90 min. The reaction mixture was then diluted with ether and was washed three times with water. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil (yield 79%). MS (m/e): 221.3 (M+, 15%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH3:23])[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])(=[O:13])=[O:12].Br[CH2:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.Cl>CN(C)C=O.O>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][N:19]([CH2:25][CH2:26][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:18]1=[O:22])[CH3:23])(=[O:13])=[O:12]
Reactant: N#Cc1ccc(CCBr)cc1
Reactant: CN(CCN1CCNC1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCN1CCN(CCc2ccc(C#N)cc2)C1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
34 mg (0.84 mmol) of NaH (60%) were added to a solution of 290 mg (0.82 mmol) of 2,3-dichloro-N-methyl-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzenesulphonamide in 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes. 177 mg (0.84 mmol) of 4-(2-bromoethyl)benzonitrile were then added. The reaction mixture was stirred at 50° C. overnight. The mixture was then poured into water, 1 N HCl was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 0-3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:35])[NH:12][C:13]1[C:14]([CH3:34])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31](=[NH:33])[NH2:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:9].C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:35])[NH:12][C:13]1[C:14]([CH3:34])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([NH:32][C:45](=[O:47])[CH3:46])=[NH:33])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cc1noc(-c2ccc(-c3ccc(CC(=N)N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC(=N)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2)cc1
Temperature: 25 °C

Procedure:
To [5-(4′-carbamimidoylmethyl-biphenyl-4-yl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester (0.055 g, 0.12 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (0.052 mL, 0.3 mmol), followed by acetyl chloride (0.009 mL, 0.126 mmol), and the reaction was stirred at room temperature. Additional acetyl chloride (0.009 mL, 0.126 mmol) was added, and the reaction was stirred at room temperature. The mixture was quenched with water and extracted with dichloromethane. The combined organic layers were dried, filterd, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>>[I:25][C:26]1[CH:27]=[C:28]([NH:29][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: Nc1cccc(I)c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4cccc(I)c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 3-iodoaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 535 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:24]>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][CH:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:24])=[O:2])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: N
Reactant: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Solvent: CO
Product: NC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 65 °C

Procedure:
To 2-(4-Chloro-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester (750 mg) is added 10 mL of a 1.0 M solution of ammonia in methanol. The reaction is heated for 48 h at 65° C., cooled to room temperature, and the solvent removed. The resultant solid is first triturated with ethyl acetate, filtered, and then triturated with methylene chloride to provide the title compound. 1HNMR (400 MHz, CD3OD) 2.70 (dd, 1H, J=14.0 Hz and 9.6 Hz), 3.01 (dd, 1H, J=14.0 Hz and 5.4 Hz), 3.95 (dd, 1H, J=9.0 Hz and 5.0 Hz), 7.05–7.15 (m, 5H), 7.32–7.36 (m, 2H), and 7.53–7.56 (m, 2H). MS 339.1 m/z (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:45]=[CH:44][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH2:37])[CH:31]=2)\[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:45]=[CH:44][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH2:37])[CH:31]=2)\[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1
Reactant: C=C(c1ccccc1)c1cccc(/C(=N/OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(c1ccccc1)c1cccc(/C(=N/OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-2-[4(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[3-(1-phenylvinyl)phenyl]acetate (780 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[3-(1-phenylvinyl)phenyl]acetic acid (701 mg, yield 95%) as colorless crystals. m.p. 171-172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])([CH3:45])([CH3:44])[CH3:43].ClCCCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:42]([S:46]([NH:49][C:24]([C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=3[CH:17]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25])(=[O:48])=[O:47])([CH3:45])([CH3:44])[CH3:43]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NS(=O)(=O)C(C)(C)C)c3)cc12
Yield: 30.6 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and tert-butylsulfonamide (37 mg, 0.27 mmol). 1,2-Dichloroethane (1 mL) and DMF (0.3 mL) were added, the vial was capped, and the reaction was stirred at r.t. overnight. The reaction was concentrated, filtered, purified by prep HPLC, and concentrated on a SPEEDVAC® to give 14 mg (31% yield) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (s, 1H) 7.97 (s, 1H) 7.91 (dd, J=8.55, 5.19 Hz, 2H) 7.84 (d, J=7.63 Hz, 1H) 7.79 (d, J=7.32 Hz, 1H) 7.46-7.59 (m, 3H) 7.19 (t, J=8.55 Hz, 2H) 6.04 (br. s., 1H) 2.99 (d, J=4.58 Hz, 3H) 1.54 (s, 9H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.71 min, (ES+) m/z (MH+)=509. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: PHENOMENEX® Gemini C18, 4.6 mm, 3 μm, Rt=16.49 min, purity=100%; column: Waters XBridge phenyl 4.6×150 mm, 3.5 μm, Rt=15.35 min, purity=100%.
Reaction SMILES: CS(C)=O.[CH3:5]C(C)([O-])C.[Na+].[C:11]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:15][CH:14]=1)#[N:12].CC(OC)(C)C>[Cl-].[Na+].O>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:5][C@H:20]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:15][CH:14]=1)#[N:12]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1ccc(C#N)cc1
Reaction time: 16 h
Yield: 55.3 %

Procedure:
A round bottom flask was charged with (CH3)3S(I)O (37.9 g, 172.4 mmol, 2 eq.) and DMSO (450 mL). With moderate stirring under N2, a clear yellow solution was formed. To this solution was added sodium tert-butoxide (16.5 g, 172.4 mmol, 2 eqs) and the resultant mixture was stirred at RT for 2 h. 21A (20 g, 86.2 mmol, 1 eq) was charged and the container of the acrylate was rinsed forward with DMSO (50 mL). Stirring of the reaction mixture was continued at RT for 16 h. The reaction mixture was analyzed for completion using 1H NMR spectroscopy. After confirming completion of the reaction, the reaction mixture was diluted by sequential addition of MTBE (500 mL) and brine (300 mL). The organic layer was separated, dried over MgSO4 and evaporated to dryness to give crude product. The crude product was purified by flash chromatography, eluting with 5-10% EtOAc in heptanes to give 11.6 g 21B (54% yield) (which was found by 1H NMR to contain a small amount of impurities). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.29 (m, 1H) 1.49 (s, 9H) 1.57-1.69 (m, 1H) 1.83-1.96 (m, 1H) 2.40-2.53 (m, 1H), 7.18 (d, 2H) 7.56 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.Cl.[OH:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>C(OCC)(=O)C>[ClH:1].[Cl:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[CH2:15][NH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)[C:2]([N:29]2[CH2:30][CH2:31][CH2:32][C@@H:27]([OH:26])[CH2:28]2)=[N:3][N:4]=1
Reactant: O[C@@H]1CCCNC1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nnc(N3CCC[C@@H](O)C3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
A mixture of 1.0 g 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 1.92 g (R)-(+)-3-hydroxypiperidine hydrochloride, 1.80 g diisopropyl ethylamine and 12 ml 1-methyl-2-pyrrolidone was stirred at 170° C. for 1 hr and 15 min. After cooling, ethyl acetate was added to the reaction solution which was then washed with water and brine. It was dried over anhydrous sodium sulfate, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography. The resulting free compound was suspended in acetic acid/ethanol/water, 1 N aqueous hydrochloric acid was added thereto, and it was dissolved by heating. After cooling, the resulting crystals were collected by filtration to give 860 mg of the title compound as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:20][O:21][CH2:22]Cl>O1CCCC1.ClCCl>[CH3:20][O:21][CH2:22][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(O)no1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C(=O)OC)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of 2.0 g (14.0 mmol) of methyl 3-hydroxy-5-isoxazole carboxylate and 29.2 ml (16.8 mmol) of N,N-diisopropylethylamine in 20 ml of tetrahydrofuran was treated with 1.27 ml of chloromethyl methyl ether. After being stirred at ambient temperature for 2 h, the solution was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 10% methanol in dichloromethane provided 129.6 mg (78%) of the desired compound as a white solid. 1H NMR (CDCl3) δ 3.57 (s, 3H), 3.96 (s, 3H), 5.37 (s, 2H), 6.64 (s, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[N:27][OH:28])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[O-]Cl.[Na+].CCN(CC)CC.[CH:43]#[C:44][CH2:45][CH2:46][CH3:47]>C(Cl)Cl.O>[C:9]([O:8][CH2:7][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:43]=[C:44]([CH2:45][CH2:46][CH3:47])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: C#CCCC
Reactant: CC(=O)NC(CCc1ccc(-c2ccc(C=NO)cc2)cc1)(COC(C)=O)COC(C)=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(-c2ccc(-c3ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of acetic acid 2-acetoxymethyl-2-acetylamino-4-[4′-(hydroxyimino-methyl)biphenyl-4-yl]butyl ester (0.2 mmol), NaOCl (2 mmol), Et3N (3 mmol) and pentyne (40 mmol) in DCM (4 mL) and H2O (1 mL) is stirred at room temperature for 12 h. It is diluted with DCM (5 mL) and H2O (10 mL) and the organic phase is washed with brine and dried over Na2SO4. After concentrating, the crude product is purified by column chromatography using EtOAc/hexane (1/1) to give the desired product as a white solid. MS: (ES+): 507.2 (M+1)+.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1([CH2:30][CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:29][CH:28]=[CH:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:36]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:37][CH:38]=2)[CH2:25][CH:26]=[CH:27][CH2:28][CH2:29]1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CCN2CC=CCC2)cc1
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CCN2CC=CCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[2-(3,6-dihydro-2H-pyridin-1-yl)-ethyl]-aniline.