Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=O)[CH:5]([NH:11]C(=O)C)[C:6]([O:8]CC)=[O:7])C.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])CCl.CC[O-].[Na+].[OH-].[K+].Cl>CCO.O>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH2:11]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: ClCc1ccc(Cl)c(Br)c1
Agent: CC[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N[C@@H](Cc1ccc(Cl)c(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 39.3 %

Procedure:
To a solution of 2-acetylamino-malonic acid diethyl ester (15.1 g, 70 mmol) and 3-bromo-4-chlorobenzyl chloride (16.7 g, 70 mmol) in EtOH (110 mL) was added a solution of NaOEt (20% in EtOH, 28.7 mL, 73 mmol). The mixture was heated at reflux for 3 h in a flask fitted with a reflux condenser, then was treated with additional 2-acetylamino-malonic acid diethyl ester (3.0 g, 14 mmol) and NaOEt (20% in EtOH, 2.0 mL, 5.1 mmol). The mixture was heated at reflux for an additional 3 h. The mixture was cooled to rt and treated with water (200 mL). The resulting white precipitate was collected by filtration, washed with water, and suspended in a mixture of water (60 mL) and EtOH (60 mL). This mixture was heated to reflux temperature in a flask fitted with a reflux condenser. A solution of KOH (3.3 g, 59 mmol) in water (10 mL) was added dropwise. After 2 h at reflux, more KOH (5.9 g, 105 mmol) in water (20 mL) was added dropwise, and the mixture was heated at reflux for 3 h. The mixture was cooled to 0° C., diluted with water (120 mL), and treated with 50% aq. HCl until pH˜1. The resulting white precipitate was collected by filtration and washed with 0.1 M HCl. The solid was suspended in water (80 mL) and treated with 2 M aq. KOH until pH˜8.0. The solution was filtered. The filtrate was warmed to 40° C., treated with Acylase “Amano” (0.19 g, Amano Enzyme Inc., Japan) and CoCl2 (10 mg), and 2 M aq. KOH was added to keep the pH of solution at 8.0. After 4 d at 40° C., 2 M HCl was added until pH=1. The suspension was filtered and the filtrate was concentrated to 20 mL. The pH was adjusted to 6.0 with 2.0 M KOH. The mixture was kept at 0° C. overnight and the solid was collected by filtration to obtain the title compound as a light tan solid (7.67 g, 40% overall). 1H NMR (400 MHz, DMSO-d6): 7.66 (br s, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 3.39 (dd, J=7.1, 5.3 Hz, 1H), 3.08 (dd, J=14.2, 4.6 Hz, 1H), 2.86 (dd, J=14.0, 7.7 Hz, 1H). To determine the enantiomeric ratio, the product was transformed to the corresponding methyl ester (SOCl2, MeOH, rt) and then to the Mosher's amide (Mosher's acid chloride, iPr2NEt, CH2Cl2). The analysis of 1H-NMR data of the amide showed that the product was a single enantiomer (e.e. >99.5%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=O.[I-].[Na+].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O>[N:15]([CH2:2][C:3]1[O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)Nc1ccccc1O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1nc2ccccc2o1
Reaction time: 0.5 h

Procedure:
To a mixture of 8.34 g (49.8 mmol) of 2-chloro-N-(2-hydroxyphenyl)acetamide (PREPARATION 4) and 0.75 g (5 mmol) of sodium iodide in 25 ml of DMSO were added 3.56 g (5.47 mmol) of sodium azide. A moderate exotherm ensued. After stirring for 30 min the reaction was partitioned between ethyl ether and saline. The organic layers were dried over magnesium surfate and concentrated. The crude product was chromatographed on silica gel (700 ml) eluting with ethyl acetate/hexane (5/95), the appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 4.60, 7.39, 7.56, 7.76 δ.
Reaction SMILES: Br.S([O-])(O)=O.[Na+].[CH2:7]([N:11]1[C:16](=[O:17])[CH:15]=[N:14][N:13]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:12]1=[O:38])[CH2:8][CH2:9][CH3:10]>O.C(O)(=O)C>[CH2:7]([N:11]1[C:16](=[O:17])[CH:15]=[N:14][N:13]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[C:12]1=[O:38])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCn1c(=O)cnn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCn1c(=O)cnn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reaction time: 5 h
Yield: 50.2 %

Procedure:
To a stirred mixture of 300 parts of a hydrobromic acid solution 48% in water, 100 parts of a hydrobromic acid solution in acetic acid and 2 parts of sodium hydrogen sulfite were added 18.9 parts of 4-butyl-2-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione. Stirring was continued for 5 hours at reflux temperature. After cooling, the precipitated product was filtered off and dissolved in a mixture of water and methanol. The mixture was neutralized with a saturated sodium hydrogen carbonate solution. The precipitated product was filtered off and crystallized twice; first from 4-methyl-2-pentanone and then from 1-propanol. The product was filtered off and dried in vacuo at 75° C., yielding 9.1 parts (50.2%) of 4-butyl-2-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione; mp. 202.3° C. (compound 10.05).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH2:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC[C@H]1CC[C@H](CCC=Cc2ccc(OCCCC)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(OCCCC)cc2)CC1
Yield: 83.7 %

Procedure:
A mixture of 19 g of 1-butyloxy-4-[4-(trans-4-pentyl-cyclohexyl)-1-butenyl]benzene (cis/trans mixture), 200 ml of absolute toluene and 100 ml of absolute ethyl acetate: was treated with 2 g of palladium/carbon (10%) and hydrogenated at normal pressure and room temperature until the hydrogen uptake came to a standstill. The inorganic material was removed by filtration and the filtrate was concentrated. The residue was purified by chromatography on silica gel with toluene/ethyl acetate. Recrystallization from ethanol gave 16 g of pure 1-butyloxy-4-[4-(trans-4-pentylcyclohexyl)-l-butyl]benzene with m.p. (C-SB) 29° C. and cl.p. (SB --I) 43° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH3:17])=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1)[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([C:54](=[O:59])NCOC)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([C:54]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)=[O:59])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncn(C)c2n1
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (500 mg, 1.38 mmol) and TMEDA (312 μL, 2.07 mmol) in THF (10 mL) at −78° C. was added n-BuLi (660 μL, 1.65 mmol, 2.5M solution in hexanes) and the resulting mixture stirred for 30 min before the addition of a solution of 4-(methoxymethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (564 mg, 2.07 mmol) in THF (5 mL). The resulting mixture was stirred for 2 h then quenched with H2O and extracted with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated with EtOAc:cyclohexane and the mother liquors concentrated in vacuo affording the title compound as an oil (760 mg, 96%). LCMS (method A): RT 3.67 min [M+H]+ 557.3
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].[CH3:15][NH2:16]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:16][CH3:15])=[O:6]
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Reactant: CN
Product: CNC(=O)c1cc(O)cc(C(F)(F)F)c1

Procedure:
Prepared from 3-hydroxy-5-(trifluoromethyl)benzoic acid and methylamine using the method of preparation 58 to give the title compound as a pale orange solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:37]=[C:36]([F:38])[C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:27]([F:39])[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:37]=[C:36]([F:38])[C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:27]([F:39])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Fc1cc(Br)cc(F)c1OC1CCOCC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1cc(F)c(OC2CCOCC2)c(F)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-(4-bromo-2,6-difluoro-phenoxy)-tetrahydro-pyran (Intermediate 18) in analogy to Example 1a): MS (ISP): 516.1 and 518.1 (M+H)+, 416.2 and 418.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:38])[C:11]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5([NH:31]S(C(C)(C)C)=O)[CH2:30][O:29][CH2:28]5)=[CH:23][CH:22]=4)=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:13][C:14]=3[C:5]2=[N:4][N:3]1COCC[Si](C)(C)C.Cl.O1CCOCC1>CO>[NH2:31][C:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:11]3[C:10](=[O:38])[C:9]4[CH:8]=[CH:7][N:6]5[C:2](=[O:1])[NH:3][N:4]=[C:5]5[C:14]=4[O:13][C:12]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=2)[CH2:30][O:29][CH2:28]1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)n(COCC[Si](C)(C)C)nc45)c3=O)cc2)COC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)[nH]nc45)c3=O)cc2)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a stirred solution of 2-methyl-propane-2-sulfinic acid (3-{-4-[3,6-dioxo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-oxetan-3-yl)-amide (46 mg, 0.07 mmol) in MeOH (6 mL) was added a solution of HCl in dioxane (4 M, 0.14 mL, 0.56 mmol) at RT. After 1 h, the reaction mixture was evaporated to dryness. The residue was suspended in DCM (5 mL), cooled in an ice bath, and TFA (1 mL) was added. The mixture was stirred at RT for 1 h before evaporating to dryness. The residue was dissolved in MeOH and loaded on to a 2 g SCX-2 cartridge. The cartridge was washed with MeOH before eluting with 2 M NH3 in MeOH solution. The eluent was collected and evaporated. The resulting residue was subjected to flash chromatography (SiO2, gradient 10 to 30% 2 M NH3/MeOH in DCM) to afford the title compound (15 mg, 52%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J=7.2 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.44-7.36 (m, 5H), 7.22 (d, J=8.2 Hz, 2H), 6.97 (d, J=7.2 Hz, 1H), 4.70 (d, J=6.1 Hz, 2H), 4.66 (d, J=6.1 Hz, 2H). LCMS (Method E): RT=2.35 min, [M+H]+=427.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]=1O.CCN(C(C)C)C(C)C.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CN(C)C=O.Cl.O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]1[O:6][C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][C:20]=2[N:19]=1)[CH:11]=[O:12]
Reactant: O=Cc1ccc(C(=O)O)c(F)c1
Reactant: Nc1cc(Oc2ccccc2)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2nc3cc(Oc4ccccc4)ccc3o2)c(F)c1
Reaction time: 0.5 h

Procedure:
To a slurry of 2-fluoro-4-formylbenzoic acid (0.500 g, 3.0 mmol) in 8 mL DCM was added 2 drops N,N-dimethylformamide (0.011 g, 0.15 mmol), followed by oxalyl dichloride (0.39 mL, 4.5 mmol). After 30 min, the reaction became clear, light yellow, and homogeneous. The reaction was evaporated and dried in vacuo. The resulting solid was suspended in 10 mL THF, and 2-amino-4-phenoxyphenol (0.60 g, 3.0 mmol) was added as a solid followed by Hunig's base (0.67 mL, 3.9 mmol). The resulting brown solution became warm, and was allowed to stir for overnight. The reaction was diluted with DCM and 1N HCl. The aq. layer was extracted 1×DCM, and the organics were dried over sodium sulfate, filtered, and concentrated to give a brown solid. This was treated with 4-methylbenzenesulfonic acid hydrate (0.85 g, 4.5 mmol) and 10 mL toluene. The reaction was fitted with a water-cooled reflux condensor and drying tube, and placed in a 120° C. bath for ˜4 h, cooled and partitioned between DCM and 1N NaOH with stirring. The reaction was filtered, and the aq. layer was extracted 1×DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated to give an orange oil which was purified by ISCO, 0-30% EtOAc/hexanes to give title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.10 (s, 1H), 8.45 (t, J=7.5 Hz, 1H), 7.94-8.02 (m, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.37-7.46 (m, 2H), 7.22 (dd, J=8.8, 2.3 Hz, 1H), 7.15 (t, J=7.3 Hz, 1H), 7.04 (d, J=8.5 Hz, 2H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([C:19](=[O:38])[CH2:20][C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=2[S:23](=[O:37])(=[O:36])[N:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[OH:3][C:4]1[C@H:6]2[C@H:7]([CH2:8][CH2:9][CH2:10]2)[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:19](=[O:38])[C:20]=1[C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][C:24]=2[S:23](=[O:37])(=[O:36])[N:22]=1
Reactant: CCOC(=O)C1CCCC1N(Cc1ccccn1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccccn3)C1=O)N2
Temperature: 60 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A solution of 2-{[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-pyridin-2-ylmethyl-amino}-cyclopentanecarboxylic acid ethyl ester (0.043 g, 0.076 mmol) in ethanol (5 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.114 mL) and stirred for 16 h at 60° C. Glacial acetic acid (0.100 mL) was added, the solvents were removed in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(4-hydroxy-2-oxo-1-pyridin-2-ylmethyl-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (8.7 mg, 0.017 mmol, 22.4%), as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.47-1.71 (3H, m), 1.99-2.15 (3H, m), 3.06 (3H, s), 3.97-4.03 (1H, m), 4.61-4.65 (1H, m), 4.99 (1H, d, J=15.3 Hz), 7.32-7.35 (1H, m), 7.42 (1H, d, J=7.8 Hz), 7.49-7.52 (1H, m), 7.56-7.58 (2H, m), 7.80-7.84 (1H, m), 8.54 (1H, d, J=4.7 Hz), 10.18 (1H, s). LC-MS (ESI) calcd for C22H23N5O6S2 517.11, found 518.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].I[CH3:13]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:13])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
A 250-mL single-necked round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 24 (1.00 g, 4.77 mmol) and DMF (15 mL). Sodium hydride (60% by weight in oil: 229 mg, 5.73 mmol) was added in one portion. After stirring at room temperature for 10 minutes, iodomethane (1.02 g, 7.16 mmol) was added and the reaction stirred at room temperature for 1.5 h. The reaction was then quenched with aqueous saturated sodium bicarbonate (10 mL) and the resulting solution poured into water (150 mL). The mixture was then extracted with ethyl acetate (250 mL). The organic layer was dried over sodium sulfate. The drying agent was then removed by filtration, and the filtrate was concentrated under reduced pressure to residue. Purification by column chromatography afforded 25 in a 68% yield (722 mg) as a white solid: mp 107-108° C.; 1H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([C:9]2[C:10]3[CH:19]=[CH:18][NH:17][C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:8]=1.[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH3:15][N:13]1[CH:14]=[C:9]([C:7]2[CH:8]=[C:3]([CH2:2][N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)[CH:4]=[CH:5][C:6]=2[O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]2[CH:19]=[CH:18][NH:17][C:11]=2[C:12]1=[O:16]
Reactant: c1cn[nH]c1
Reactant: Cn1cc(-c2cc(CO)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Cn3cccn3)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
A mixture of Example 20b (0.04 g, 0.115 mmol), 1H-pyrazole (0.016 g, 0.231 mmol), and triphenylphosphine (0.061 g, 0.231 mmol) in tetrahydrofuran (1 mL) was stirred for 2 minutes. To this solution was added di-t-butyl azodicarboxylate (DTBAD, 0.053 g, 0.231 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (C18, 10-80% acetonitrile/water with 0.1% TFA) to afford 0.006 g of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 3.49 (s, 3H), 5.37 (s, 2H), 5.21 (t, J=5.8 Hz, 1H), 6.17-6.18 (m, 1H), 6.28 (t, J=1.98 Hz, 1H), 6.86 (d, J=7.63 Hz, 2H), 6.97 (d, J=8.24 Hz, 1H), 7.02 (t, J=7.32 Hz, 4H), 7.22-7.29 (m, 5H), 7.39 (d, J=2.14 Hz, 1H), 7.47 (d, J=1.83 Hz, 1H), 7.53-7.46 (m, 3H), 7.86 (d, J=2.44 Hz, 1H), 11.97 (s, 1H). (ESI+) m/z 397.2 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Sn:19]([CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33])([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Sn:19]([C:32]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)C(O)c1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)C(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 0.29 h
Yield: 36.2 %

Procedure:
This example demonstrates the synthesis and purification of the acylstannane complex Bu3SnC(O)Ph. In a nitrogen-filled glove box, a 250 mL three-neck round bottom flask was charged with diisopropylamine (1.31 g, 13.0 mmol) and 40 mL dry THF. The solution was cooled to about −30° C. and 2.5 M BuLi in hexane (5.2 mL, 13.0 mmol) was added slowly by syringe. The reaction mixture was allowed to warm to room temperature. A dropping funnel containing Bu3SnCH(OH)Ph (5.00 g, 12.6 mmol) dissolved in 20 mL dry THF, a nitrogen inlet, and a glass stopper were attached to the round bottom flask. The apparatus was removed from the glove box. The reaction setup was connected to a nitrogen-filled Schlenk line. The reaction mixture was cooled to about −78° C., and the Bu3SnCH(OH)Ph/THF solution was added dropwise. After the addition, the reaction mixture was allowed to stir for 15-20 min at −78° C., during which time the color changed from yellow to light orange. The glass stopper was then removed, and 1,1′-(azo dicarbonyl)dipiperidine (3.18 g, 12.6 mmol) was quickly added as a solid. The resulting reaction mixture was allowed to stir for 20-30 min at −78° C., during which time the reaction mixture turned dark orange. The reaction mixture was allowed to warm to about 0° C., and stirred for approximately 30 min at that temperature. The reaction was quenched at 0° C. by the addition of approximately 14 mL saturated ammonium chloride; solids formed in the reaction mixture. The reaction mixture was brought into a nitrogen-filled glove-box, filtered, dried (MgSO4), and concentrated to afford an orange oil. Chromatography on silica gel using 95/5 hexane/ethyl acetate as the eluent afforded 1.80 g of Bu3SnC(O)Ph as a yellow-orange oil. 1H NMR(C6D6) δ7.9 (2H, d, Hortho), 7.3 (3H, mult, Hmeta & Hpara), 1.8-0.9 (27H, Bu's); 119Sn NMR (CDCl3) δ 87.4 relative to SnMe4; 13C NMR (CDCl3) δ244.8 (CO), 142.9, 132.8, 128.8, 127.7 (Caromatic), 29.1, 27.3, 13.6, 11.5 (Cbutyl).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[CH:4](O)[C:5]([OH:7])=[O:6].[C:14]1([CH:21]=[CH:20][C:18](O)=[CH:17][CH:16]=1)[OH:15].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:15][C:14]1[CH:16]=[CH:17][C:18]2[O:7][C:5](=[O:6])[CH:4]([C:3]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:2]=3[CH3:1])[C:20]=2[CH:21]=1
Reactant: Oc1ccc(O)cc1
Reactant: Cc1ccc(C)c(C(O)C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(C2C(=O)Oc3ccc(O)cc32)c1

Procedure:
By the method described in GB 2068402A 2,5-dimethylmandelic acid (65 parts) was reacted with hydroquinone (33 parts) and 98% sulfuric acid (32 parts) and toluene (440 parts) to give 5-hydroxy-2-oxo-3-(2,5-dimethylphenyl)-2,3-dihydrobenzofuran (33 parts) which was isolated by crystallisation and chromatography. The 1Hnmr spectrum of the purified product was consistent with structure.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.Cl[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCCNc2ccc3c(c2)OCO3)cc1
Yield: 75.3 %

Procedure:
3,4-Methylenedioxyaniline (1.80 g), methyl 4-(3chloropropoxy)benzoate (2.0 g) and sodium bicarbonate (1.47 g) in toluene (20 ml) were heated with stirring under refluxing for 29 hours. The reaction solution was concentrated under reduced pressure, and thereto were added water and an equivalent amount of conc. hydrochloric acid, then, the resulting precipitate was collected by filtration. After washed with water, the precipitate was recrystallized from aqueous methanol to give the desired product (2.17 g). mp. 124°-127° C.