Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]3[C:23](=[O:31])[C:24](=[O:30])[C:25]=3OC(C)C)[CH:9]=2)[O:4][C:3]1([CH3:33])[CH3:32].[CH2:34]([CH2:36][NH2:37])[OH:35]>CC#N.O>[OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]3[C:23](=[O:31])[C:24](=[O:30])[C:25]=3[NH:37][CH2:36][CH2:34][OH:35])[CH:9]=2)[O:4][C:3]1([CH3:32])[CH3:33]
Reactant: CC(C)Oc1c(-c2ccc3c(c2)[C@@H](N2Cc4ccccc4C2=O)[C@H](O)C(C)(C)O3)c(=O)c1=O
Reactant: NCCO
Solvent: O
Solvent: CC#N
Product: CC1(C)Oc2ccc(-c3c(NCCO)c(=O)c3=O)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Temperature: 50 °C
Yield: 23.4 %

Procedure:
A solution of 529 mg(1.18 mmol) of 3-[trans-3-hydroxy-2,2-dimethyl-4-(1-oxo-1,3-dihydroisoindol-2-yl)-chroman-6-yl]-4-isopropoxy-cyclobut-3-ene- 1,2-dione as prepared in Example 3 in CH3CN (20 mL) and ethanolamine (716 μL; 11.8 mmol) was stirred at room temperature for 4 days. The reaction mixture was heated at 50° C. for 1 h, cooled to room temperature, diluted with H2O, and extracted into 20% THF/CH2Cl2. The organic extracts were dried over MgSO4 and purified by flash chromatography (CH2Cl2 : MeOH :NH4OH (93.25; 4.5; 2.25)) followed by trituration from MeOH/ether to give 124 mg of the title compound as a tan solid, mp 205°-215° C.: 1H-NMR (DMSO-d6 ; 400 MHz) δ8.93 (t, 1 H), 7.79 (dd, 1 H), 7.74 (s, 1 H), 7.69 (dd, 1 H), 7.5-7.64 (m, 3 H), 7.00 (d, 1 H), 5.75 (d, 1 H), 5.2-5.5 (br, 1 H), 4.86 (t, 1 H), 4.4-4.5 (br d, 1 H), 3.67 (m, 2 H), 3.53 (q, 3 H), and 1.27 ppm (s, 3 H); IR (KBr) 1780, 1710, 1660, and 1600 cm-1 ; mass spectrum (+FAB), m/e 449 (M +H), and 471 (M+Na). Anal. Calcd. for C25H24N2O6. 1 H2O C, 64.37; H, 5.62; N, 6.01 Found: C, 64.32; H, 5.83; N, 6.18.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[C:25]1([CH:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:25]1([CH:31]([NH:33][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:13])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(N)c1ccccc1
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)c1ccc2cnccc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1-phenylethylamine (56.1 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a clear oil (78.7 mg, 99%).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:34]=[CH:33][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[C:21]=3[Cl:31])[CH:14]=[CH:15][C:16]=2[F:17])=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[CH:8]=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:32])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[C:21]=4[Cl:31])[CH:14]=[CH:15][C:16]=3[F:17])[CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(F)c(Oc3ccc(N)cc3)c2)c1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(F)c(Oc3ccc4nc(N)sc4c3)c2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of potassium thiocyanate (1.65 g, 17.0 mmol) in acetic acid (15 mL) was added a solution of N-[3-(4-aminophenoxy)-4-fluorophenyl]-2-chloro-3-(1-cyano-1-methylethyl)benzamide (1.75 g, 4.13 mmol) in acetic acid (5 mL), and the mixture was stirred at room temperature for 15 min. To the obtained solution was added dropwise a solution of bromine (726 mg, 4.54 mmol) in acetic acid (15 mL) at room temperature over 30 min or longer. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hr. The resulting yellow solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL) and ethyl acetate (200 mL), and basified with 2N aqueous sodium hydroxide solution. The aqueous layer was separated, and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (854 mg, 43%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]=[S:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16].O>CCOCC>[NH2:16][CH2:15][CH2:14][NH:17][C:12]([NH:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[S:13]
Reactant: NCCN
Reactant: COc1cc(N=C=S)cc(OC)c1
Solvent: CCOCC
Solvent: O
Product: COc1cc(NC(=S)NCCN)cc(OC)c1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A slurry of 9.75 g (0.05 mole) of 3,5-dimethoxyphenyl isothiocyanate in 27 ml of ether was added dropwise to a stirred solution of 3.0 g (0.05 mole) of ethylenediamine at room temperature. A five-degree rise in temperature was noted at the start of the one hour addition period. A solid appeared during the addition, and stirring was continued for 2.5 hours. The batch was allowed to stand overnight, and 100 ml of H2O was added. The solid was removed by filtration and the filtrate acidified with 4.5 ml of concentrated HCl and evaporated to dryness on the steam bath. The residue was sonicated with 100 ml of water and warmed to 50° C. for 10 minutes. This was filtered and basified to pH 10 with 10% NaOH. This gave 2.6 g of 14, m.p. 125°-126° C. Analysis satisfactory for C11H17N3O2S.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][S:13]2(=[O:19])=[O:18])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.CO.N([O-])=[O:24].[Na+]>O>[O:18]=[S:13]1(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][N:12]1[C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([OH:24])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)cc(N2CCCCS2(=O)=O)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(O)cc(N2CCCCS2(=O)=O)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 3.8 %

Procedure:
To a solution of methyl 3-amino-5-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)benzoate (D267) (7.5 g, 26.4 mol, 1 equiv) in a 2N aqueous HCl solution (75 ml) and MeOH (75 ml) at 0° C. was added NaNO2 (4.0 g, 58.1 mmol, 2.2 equiv) portionwise over 20 min. MeOH (50 ml) and H2O (200 ml) were added and the resulting mixture was stirred at 95° C. for 1 h then cooled to room temperature. Most of the MeOH was removed in vacuo and the resulting aqueous phase was extracted with AcOEt. The insoluble material was filtered off to give methyl 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-5-hydroxybenzoate (D) (0.63 g, 8%). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown residue which was redissolved in AcOEt. The organic phase was extracted with a saturated aqueous Na2CO3 solution and the aqueous phase was extracted three times with Et2O then acidified to pH 1 and re-extracted three times with AcOEt. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give methyl 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-5-hydroxybenzoate (D268) (2.2 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28](=[N:30][OH:31])[CH3:29])=[N:9]1.[OH-].[K+].Cl.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38]Cl.CS(C)=O>O>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][O:31][N:30]=[C:28]([C:10]1[CH:11]=[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)[CH3:29]
Reactant: CC(=NO)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(=NOCCN(C)C)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
A mixture of 1-[1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]ethanone oxime (196 mg, 0.415 mmol), KOH (142 mg, 2.3 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (185 mg, 1.3 mmol), and anhydrous DMSO (5 mL) was stirred at 60° C. in a sealed vial for 3 h. The reaction mixture was diluted with water, extracted with ether. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-30% MeOH/DCM) to give the title compound as a white solid (50 mg, 22%). 1HNMR (CDCl3): δ8.04 (d, 1H), 7.83-7.81 (m, 1H), 7.74-7.71 (m, 1H), 7.57-7.43 (m, 5H), 7.21 (d, 1H), 7.00 (s, 1H), 6.76 (d, 1H), 4.38 (t, 2H), 3.07 9s, 3H), 2.78 (m, 2H), 2.40 (brs, 6H), 2.31 (s, 3H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([C@H:22]1[O:30][C@H:29]2[C@H:25]([N:26]=[C:27]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[S:28]2)[C@@H:24]([O:40][CH2:41][CH:42]=[CH2:43])[C@@H:23]1[O:44][CH2:45][CH:46]=[CH2:47])(=[O:21])[CH3:20].[Si]([C:52]([F:55])([F:54])[F:53])(C)(C)C>C1COCC1>[CH2:45]([O:44][C@@H:23]1[C@@H:22]([C@@:19]([OH:21])([CH3:20])[C:52]([F:55])([F:54])[F:53])[O:30][C@H:29]2[C@H:25]([N:26]=[C:27]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[S:28]2)[C@H:24]1[O:40][CH2:41][CH:42]=[CH2:43])[CH:46]=[CH2:47]
Reactant: C=CCO[C@@H]1[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@H](C(C)=O)[C@H]1OCC=C
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@H]([C@](C)(O)C(F)(F)F)[C@H]1OCC=C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of TBAF (3.7 g, 14 mmol) and 4 Å molecule sieves in THF (200 mL) was stirred for 30 min at 0° C. followed by the addition of a solution of 118 (15 g, 35 mmol) and TMS-CF3 (20 g, 141 mmol) in THF (80 mL). After stirring for additional 12 hours at 25° C., additional TBAF (14 g, 54 mmol) was added, and the mixture was stirred for 1 hour. The reaction was quenched by brine (200 mL), extracted with ethyl acetate (3×150 mL), the organic layers combined, washed with brine (3×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 5%-25% ethyl acetate in petroleum ether to afford 119 (12 g, 69%) as a yellow oil; (ES, m/z) [M+H]+ 497.1. 1H NMR (300 MHz, CDCl3) δ 6.12-6.18 (m, 1H), 5.86-6.00 (m, 2H), 5.19-5.37 (m, 4H), 4.02-4.45 (m, 6H), 3.92-3.96 (m, 1H), 3.62-3.64 (m, 1H), 3.25 (d, J=3.6 Hz, 3H), 1.54-1.56 (m, 9H), 1.27-1.38 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC1C=CC2NN=NC=2N=1.[NH2:51][N:52]1[C:60]2[C:55](=[C:56]([F:61])[CH:57]=[CH:58][CH:59]=2)[CH:54]=[CH:53]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:61][C:56]1[CH:57]=[CH:58][CH:59]=[C:60]2[C:55]=1[CH:54]=[CH:53][N:52]2[NH:51][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][CH:10]=1)=[O:16]
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: Nn1ccc2c(F)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1ccc2[nH]nnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nn1ccc2c(F)cccc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 45.3 %

Procedure:
A solution of 2-(3-fluorophenyl)-pyrimidine-5-carboxylic acid (0.33 g), HATU (0.67 g) and hydroxyazabenzotriazole (0.26 g) in dry DMF (15 mL) is stirred at rt for 30 min under N2. A solution of 1-amino-4-fluoroindole (0.24 g) in dry DMF (5 mL) is added followed by the addition of DIPEA (0.39 mL). The mixture is stirred at 80° C. for 24 h, cooled to rt, and then concentrated in vacuo. The residue is dissolved in EtOAc and washed with water, brine and dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 60% DCM/heptane to afford 2-(3-fluorophenyl)pyrimidine-5-carboxylic acid-(4-fluoroindol-1-yl)amide (0.24 g, 53%) as a solid. MS: 351 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 6.64 (d, 1H), 6.89-6.92 (q, 1H), 7.15-7.22 (m, 1H), 7.31-7.33 (d, 1H), 7.46-7.52 (m, 1H), 7.56 (d, 1H), 7.63-7.70 (q, 1H), 8.18-8.23 (d, 1H), 8.34-8.37 (d, 1H), 9.45 (s, 2H), 12.30 (s, 1H). IC50=11 nM.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH:25][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:21]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and glycine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=164-165° C.). The product was purified by silica gel chromatography using EtOAc as the eluent, followed by recrystallization from EtOAc.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[SH:12].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: Sc1ccccn1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Sc1ccccn1
Reaction time: 1 h
Yield: 90 %

Procedure:
15.6 ml (1.2 equivalents) of propionyl chloride were slowly added at room temperature to a solution of 20 g of 2-pyridinethiol and 25.1 ml (1.2 equivalents) of triethylamine in 200 ml of anhydrous methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with ethyl acetate. The organic solution thus obtained was washed twice with a dilute aqueous solution of sodium hydrogencarbonate and then with water. The organic layer was separated and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was subjected to fractional distillation in vacuo, to give 27 g (yield 90%) of the title compound, boiling at 93° C./0.05 mmHg (6.7 Pa).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:20][C:21]3[CH:22]=[C:23]([CH2:33][CH2:34][C:35]4[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=4)[NH:24][N:25]=3)=[O:16])=[CH:18][CH:19]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCN(C(C)=O)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(C)=O)CC4)cc3)n[nH]2)cc(OC)c1
Yield: 0.9 %

Procedure:
4-(4-acetylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared as for Example 94, but starting from methyl 4-(4-acetylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 31-51% gradient of acetonitrile in water, containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (3 mg, 1.0%); 1H NMR (399.9 MHz, DMSO-d6) δ 2.06 (3H, s), 2.78 (4H, s), 3.28 (2H, s) 3.25 (2H, t), 3.49-3.56 (4H, m), 3.73 (6H, s), 6.33 (1H, t), 6.42 (2H, d), 6.45 (1H, s), 6.99 (2H, d), 7.92 (2H, d), 10.32 (1H, s), 12.08 (1H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: N#Cc1cccc(O)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 27.7 %

Procedure:
3-cyanophenol (2.38 g, 20 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.88 g, 22 mmol). The addition of sulfuric acid (20 mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(910 mg, 28%). 1H NMR (CD3COCD3): d 8.30 (d,1H), 7.67 (s,1H), 7.49 (d, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][OH:26].CCOC(/N=N/C(OCC)=O)=O.O[C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[C:42](=[O:58])[N:43]([CH:50]1[CH2:55][CH2:54][C:53](=[O:56])[NH:52][C:51]1=[O:57])[C:44]2=[O:49]>C1COCC1.CO>[O:57]=[C:51]1[CH:50]([N:43]2[C:44](=[O:49])[C:45]3[C:41](=[CH:40][CH:48]=[CH:47][C:46]=3[O:26][CH2:25][C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)[C:42]2=[O:58])[CH2:55][CH2:54][C:53](=[O:56])[NH:52]1
Reactant: OCc1ccco1
Reactant: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccco4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.7 %

Procedure:
To a solution of triphenylphosphine (630 mg, 2.4 mmol) and furan-2-yl-methanol (0.17 mL, 2.0 mmol) in THF (10 mL) was added a solution of DEAD (0.38 mL, 2.4 mmol) in THF (0.6 mL) at 0° C. After 5 min, 4-hydroxy-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (550 mg, 2.0 mmol) was added to the mixture. The mixture was allowed to warm to room temperature and kept for 4 h. The solvent was removed in vacuo, and the residue was purified by column chromatography (Silca Gel) to give an oil. The oil was slurried in methanol (10 mL) for 3 h to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(furan-2-ylmethoxy)-isoindole-1,3-dione as a yellow solid (310 mg, 44% yield): mp, 184-186° C.; 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H, CHH), 2.42-2.61 (m, 2H, CH2), 2.80-2.95 (m, 1H, CHH), 5.07 (dd, J=5, 13 Hz, 1H, NCH), 5.35 (s, 2H, CH2), 6.49 (dd. J=2, 3 Hz, 1H, Ar), 6.68 (d. J=8 Hz, 1H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.68-7.71 (m, 2H, Ar), 7.83 (t J=8 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.93, 48.77, 62.55, 110.72, 111.38, 115.72, 116.64, 120.35, 133.35, 136.89, 143.99, 149.15, 155.12, 165.21, 166.73, 169.88, 172.76; Anal Calcd for C18H14N2O6+0.1H2O: C, 60.71; H, 4.02; N, 7.87; H2O, 0.51. Found: C, 60.47; H, 3.97; N, 7.73; H2O, 0.38.
Reaction SMILES: CC(CCC[CH2:7][CH2:8][O:9][C:10]([C:12]1[C:17]([C:18]([O:20][CH2:21][CH2:22]CCCC(C)C)=[O:19])=CC=CC=1)=[O:11])C.C1(P(CC2C(CP(C3C=CC=CC=3)C3C=CC=CC=3)[O:46][C:45]3([CH2:65][CH2:64][CH2:63][CH2:62]3)[O:44]2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:44]1[C:45]2([CH2:65][CH2:64][CH2:63][CH2:62]2)[O:46][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]1[C:10]([O:9][CH2:8][CH3:7])=[O:11]
Reactant: CC(C)CCCCCOC(=O)c1ccccc1C(=O)OCCCCCC(C)C
Reactant: c1ccc(P(CC2OC3(CCCC3)OC2CP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C1CCCC1
Solvent: c1ccccc1
Product: CCOC(=O)C1OC2(CCCC2)OC1C(=O)OCC

Procedure:
Example 4 was repeated in which the DTDR was replaced by an equivalent amount of DODDR and the DIOP was replaced by an equivalent amount of (-)-2,3-bis(diphenylphosphinomethyl)-1,4-dioxaspiro[4,4]nonane, prepared by: (a) reacting L-(+)-diethyl tartrate with cyclopentanone in benzene in the presence of p-toluenesulphonic acid to give diethyl 1,4-dioxaspiro[4,4]nonan-2,3-dicarboxylate, b.p. 154°-158° C./6.0 mm., (b) reducing this with lithium aluminium hydride to give (-)-2,3-O-cyclopentylidene-L-threitol, b.p. 124°-130° C./0.2 mm., (c) converting this to (-)-1,4-ditosyl-2,3-O-cyclopentylidene-L-threitol m.p. 109°-115.5° C. by reaction with p-toluenesulphonyl chloride in pyridine and (d) treating with potassium and diphenylphosphine in tetrahydrofuran to give the desired compound m.p. 93°-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[CH3:44][C:45](OC(C)=O)=[O:46].[ClH:51]>C(Cl)Cl>[ClH:51].[Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:45](=[O:46])[CH3:44])[CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(Sc2cnc(Nc3nc(C4CCNCC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(C)=O)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A 20 mL vial was charged with 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine (40 mg, 0.068 mmol), triethylamine (0.0190 mL, 0.14 mmol), and CH2Cl2 (2 mL). Ac2O (0.008 mL, 0.082 mmol) was added and the reaction was stirred at room temperature for 10 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated to afford the title compound (38.2 mg, 84.2% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.20 (bs, 1H), 8.17 (d, 1H), 7.74 (m, 1H), 7.31 (m, 2H), 7.21 (t, 1H), 6.93 (d, 1H), 6.78 (m, 1H), 6.74 (s, 1H), 6.71 (m, 2H), 4.43 (d, 1H), 3.87 (d, 1H), 3.69 (s, 3H), 3.14 (m, 1H), 2.86 (m, 1H), 2.64 (m, 1H), 2.01 (s, 3H), 1.95 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci) m/z=631.4 (M+H—HCl).