Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([Br:17])=[CH:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[N+:14]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[Br:1][C:2]([Br:17])=[CH:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[NH2:14]
Reactant: O=[N+]([O-])c1ccc(OC(F)F)cc1C=C(Br)Br
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(OC(F)F)cc1C=C(Br)Br
Temperature: 25 °C
Yield: 34.2 %

Procedure:
To a suspension of 2-(2,2-dibromovinyl)-4-difluoromethoxynitrobenzene (534 mg) in ethanol (3.7 mL) was added tin (II) chloride dihydrate (742 mg) at room temperature, and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 1 mol/L Aqueous sodium hydroxide solution was added to the residue and this resulting mixture was extracted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (168 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.O1C(C2C=C(N[C:28]3[N:33]=[C:32]([C:34]4[C:35]([C:43]5[CH:44]=[C:45]([NH:49][C:50](=[O:57])[CH2:51][C:52]6[S:53][CH:54]=[CH:55][CH:56]=6)[CH:46]=[CH:47][CH:48]=5)=[N:36][N:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=45)[CH:31]=[CH:30][N:29]=3)C=CC=2)=CN=C1>CC(O)C.Cl.C(Cl)Cl>[F:14][C:11]([F:12])([F:13])[C:10]([NH:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:28]2[N:33]=[C:32]([C:34]3[C:35]([C:43]4[CH:48]=[CH:47][CH:46]=[C:45]([NH:49][C:50](=[O:57])[CH2:51][C:52]5[S:53][CH:54]=[CH:55][CH:56]=5)[CH:44]=4)=[N:36][N:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=34)[CH:31]=[CH:30][N:29]=2)[CH:3]=1)=[O:15]
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: Nc1cccc(CNC(=O)C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CNC(=O)C(F)(F)F)c3)n2)c1
Temperature: 180 °C
Yield: 67 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-2,2,2-trifluoroacetamide (46 mg, 0.21 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (75 mg, 0.17 mmol) (see Example 2, Step B) in i-PrOH (3 mL) was acidified with 2 drops of 12 N HCl and heated in a microwave for 15 min. at 180° C. The reaction mixture was then diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 67% yield. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=6.8 Hz, 1H), 8.31 (d, J=9.1 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.72-7.75 (m, 2H), 7.63 (s, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.26-7.38 (m, 7H), 7.04 (s, 1H), 6.94 (m, 1H), 6.63 (d, J=5.4 Hz, 1H), 4.48 (d, J=5.7 Hz, 2H), 3.96 (s, 2H). ES-LC/MS m/z=628 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:10])=[C:5]([C:8]#[N:9])[S:6][CH:7]=1)=[CH2:2].C1C(=O)N(Br)C(=[O:14])C1.[OH-].[Na+]>C(O)(C)(C)C.O>[CH3:10][C:4]1[C:3]([CH:1]2[CH2:2][O:14]2)=[CH:7][S:6][C:5]=1[C:8]#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1csc(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1c(C2CO2)csc1C#N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of 4-ethenyl-3-methylthiophene-2-carbonitrile (1.70 g, 11.4 mmol) in 30 mL of t-Bu-OH and 60 mL of water was added NBS (2.40 g, 13.7 mmol) portionwise. The mixture was stirred at 90° C. for 1 hour then cooled down to 10° C. Then a solution of NaOH (0.7 g in 10 mL of water, 17.5 mmol) was added dropwise and stirred for 15 minutes. The reaction mixture was extracted with EtOAc twice and concentrated. The residue was purified by silica column chromatography (petrol ether: EtOAc=20:1) to afford 3-methyl-4-(oxiran-2-yl)thiophene-2-carbonitrile.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.[CH3:18][C:19]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:20]=1[O:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1.Cl>[CH3:12][N:13]1[C:17]([C:25]([C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[CH2:22][O:21][C:20]2[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:19]=2[CH3:18])=[O:26])=[CH:16][CH:15]=[N:14]1
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)Cl)c1
Reactant: Cn1cccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccnn2C)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
Dichloroethane (20 ml), thionyl chloride (1.31 g, 0.011 mol) and N,N,-dimethylformamide (0.1 ml) were added to 2-(2,5-dimethylphenoxymethyl)benzoic acid (2.56 g, 0.01 mol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride. 1.6M n-butyllithium/n-hexane solution (6.25 ml, 0.01 mol) was added to a mixture of 1-methylpyrazole (0.99 g, 0.012 mol) and THF (10 ml) at -70 to -60° C. over 15 minutes, and then the mixture was stirred at -70° C. to room temperature for 1 hour. The reaction mixture was cooled to -70° C., and a solution of the crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride in THF (10 ml) was added, and the mixture was stirred at -70° C. for 1 hour. After completion of the reaction, IN hydrochloric acid (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone (0.50 g, 15.6%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:20][C:21]([O:23][CH3:24])=[O:22])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2c([N+](=O)[O-])cccc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-nitro-1H-indole (500 mg, 3.08 mmol) in DMF (10 ml), K2CO3 (511 mg, 3.70 mmol) and methyl 2-bromoacetate (343 μl, 3.70 mmol) were added, and the mixture was stirred at 100° C. under MW irradiation for 30 minutes. The insoluble inorganic salts was filtered off, and the solvent was evaporated, recovering crude desired methyl 2-(4-nitro-1H-indol-1-yl)acetate which was used in the next step without further purification (810 mg). MS/ESI+ 235.1 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH3:20])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[N:6][CH:7]=1.CI.[CH3:23][Si](C)(C)[N-][Si](C)(C)C.[K+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([CH3:23])([CH3:20])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(Oc1ccc(F)cn1)C(=O)OCc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(Oc1ccc(F)cn1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of benzyl 2-(5-fluoro-2-pyridyloxy)propionate (2.9 g, 10 mmol) and methyl iodide (3.3 mL, 53 mmol) in 40 mL of anhydrous THF at −78° C. was added potassium hexamethyldisilazide (0.5 M in toluene, 32 mL, 16 mmol). The reaction was allowed to warm to room temperature over 3 h and was partitioned between saturated ammonium chloride (150 mL) and EtOAc (150 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 0 to 20% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.63 (d, 1H), 7.44 (ddd, 1H), 7.27 (m, 3H), 7.18 (m, 2H), 6.74 (dd, 1H), 5.09 (s, 2H) 1.64 (s, 6H). LC-MS: m/e 290 (M+H)+ (3.7 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:26]([NH:28][C:29](=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)OC1C=CC=CC=1)#[N:27]>>[C:26]([NH:28][C:29]([NH:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)=[N:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:23])#[N:27]
Reactant: COc1ccc(CN(CCN(C)CCCCN)c2ccccn2)cc1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: COc1ccc(CN(CCN(C)CCCCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.54 g (1.6 mol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam. MS (+FAB method): m/z (rel. int. [%])=624 ([M+H]+, 1), 121 (100) IR (KBr): 2163 cm-1 (C≡N).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[NH:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:18][CH:17]=2)[CH:5]=[C:6]([F:15])[C:7]=1[O:8]C(=O)C(C)(C)C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[NH:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])=[CH:18][CH:17]=2)[CH:5]=[C:6]([F:15])[C:7]=1[OH:8]
Reactant: CC(C)S(=O)(=O)Nc1cnccc1-c1ccc(-c2cc(F)c(OC(=O)C(C)(C)C)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1cnccc1-c1ccc(-c2cc(F)c(O)c(F)c2)cc1
Yield: 50 %

Procedure:
Dissolve 2,2-Dimethyl-propionic acid 3,5-difluoro-4′-[3-(propane-2-sulfonylamino)-pyridin-4-yl]-biphenyl-4-yl ester in THF (9 ml) and ethanol (1 ml). Add NaOH 2N (10 ml) and heat the mixture to 60° C. for 7 h. Evaporate solvents and add HCl 3N to acidify the mixture. Apply the acidic mixture to 2 g SCX cartridge. Elute the SCX cartridge with methanol (×3) to remove non-basic impurities. Elute the product with 2N ammonia in methanol to afford, after evaporation, 55.2 mg of the title compound as a yellow solid (50% yield). MS (ES−): 403.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[C:10](N)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N.OS(O)(=O)=O>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.O.C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: NC(=O)c1ccccc1
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)NC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 134.2 %

Procedure:
6.4 ml of hexamethyldisilazane (31 mmoles) were added to a refluxing mixture of 15 ml of toluene, 40 mg of saccharin (0.22 mmole) and 5.0 g of benzamide (41.3 mmoles) and the ammonia liberated was led into water by a stream of nitrogen passed over the reaction mixture. Titration with 1 N H2SO4 revealed that the calculated amount of ammonia was evolved in 15 minutes and solvent and excess hexamethyldisilazane were evaporated in vacuo to obtain 8.04 g (101%) of N-trimethylsilylbenzamide melting at 111°-115° C. The experiment was repeated without the addition of saccharin and it was found that 82% of the theoretical amount of ammonia was evolved in 15 minutes and 88% of it in 50 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Sc2ccc(Br)cc2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(Cl)cc3Cl)cc2)c1C
Yield: 37.6 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,4-dichlorobenzene (0.196 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,4-dichloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.10 g, 36%) as a solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:19])=[C:15]([CH:18]=1)[CH:16]=O>>[S:9]1[C:8]([CH2:16][C:15]2[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[F:19])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=Cc1cc(Br)ccc1F
Reactant: c1ccc2sccc2c1
Product: Fc1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
Thianaphthene and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[S-:11][S-:12].[Na+].[Na+]>O>[CH:5]1[CH:4]=[C:3]([N+:8]([O-:10])=[O:9])[C:2]([S:11][S:12][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:7][CH:6]=1
Reactant: [S-][S-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1SSc1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 95 %

Procedure:
1300 parts of water containing 150 parts of castor oil ethoxylate and 250 parts of 1-chloro-2-nitrobenzene are charged to a reactor and heated to 60° C. with thorough mixing. Simultaneous addition is then made of 2268 parts of disulfide solution (preparation as described in Example 1) and 2250 parts of 1-chloro-2-nitrobenzene in separate streams. The rate of addition is 400 parts per hour. When the total amount of chloronitrobenzene has been added, the remaining amount of disulfide is added at a rate of 100 parts per hour. The reaction is slightly exothermic and the temperature is kept in the range from 60°-65° C. by cooling. During the reaction, both the continuously added chloronitrobenzene and the resultant disulfide are continuously dispersed in the reaction mixture. This is done by constant and intensive mixing. Agglomerates are comminuted with a dismembrator. After the total amount of disulfide has been added as well, stirring is continued until the reaction mass consists of individual yellow crystals and of a colourless to tea-coloured mother liquor. The batch is then cooled to 40° C. and filtered. The product is washed with cold water until the washings are colourless, affording 2,2'-dinitrodiphenyl disulfide which contains about 5% of by-products. The yield is 95%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.[OH:26]OS([O-])=O.[K+]>CC(C)=O.O>[OH:26][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]2
Reactant: O=S([O-])OO
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1

Procedure:
To a stirred solution of (S)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (6.95 mmol, 2.54 g) in Acetone (20.00 mL), a solution of Oxone(R), monopersulfate compound (7.65 mmol, 4.70 g) in Water (20 mL) was added dropwise over 2 min. The resultant solution was stirred for a further 10 min before being quenched with NaHSO3 (aq). The solution was extracted with DCM (×3), dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a pale yellow oil (2.42 g). On standing the reaction mixture solidified to a pale yellow solid in an oily residue. The solid was triturated with heptane then ether to give the title compound as an off white solid (1.66 g, 94%). MS (ESI): m/z [M−H]− 254.0
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.[CH2:12]([O:15]CC=C)[CH:13]=[CH2:14].[Na]>C(O)C=C>[CH2:12]([O:15][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)[CH:13]=[CH2:14]
Reactant: C=CCOCC=C
Reactant: Clc1ncnc2nc[nH]c12
Agent: [Na]
Solvent: C=CCO
Product: C=CCOc1ncnc2nc[nH]c12
Temperature: 100 °C
Yield: 48 %

Procedure:
Sodium (2.0 g, 86.96 mmol) was added to distilled allyl alcohol (35 ml) under nitrogen. 6-Chloropurine (1.0 g, 6.47 mmol) was dissolved in distilled allyl alcohol (35 ml) and the sodium allyloxide solution (33 ml) was added. The reaction was heated to 100° C. for 20 h, under nitrogen. After cooling, neutralisation of the reaction mixture, followed by recrystallisation of the residue from water, gave a white crystalline solid (550 mg, 48%), m.p. 199-200° C.; (Found: C, 54.35; H, 4.49; N. 32.06. Calc. for C8H8N4O: C, 54.54; H, 4.58; N, 31.80%); νmax (cm−1) 3052, 2977, 2811 (NH, C—H) δH (200 MHz, d6-DMSO) 8.526 (1H, s, C(2)H or C(8)H), 8.438 (1H, s, C(2)H or C(8)H). 6.280-6.086 (1H, dddd, CH═CH2), 5.485 (1H, dd, Jgem=1.5Hz, Jtrans=17.2 Hz, ═CH2), 5.325 (1H, dd, Jgem=1.5 Hz, Jcis=10.4 Hz, ═CH2), 5.107 (2H, d, J=5.5 Hz, OCH2); m/z 176 (M+, 43%), 174 (M+, 43%), 161 (31), 147 (39), 136 ([MH—CH2CH═CH2]+, 21%), 120 ([MH—OCH2CH═CH2]+, 49%), 108 (13), 93 (37), 81 (11), 69 (32), 66 (18), 53 (26), 41 ([CH2CH═CH2]+, 63%), 28 (62);
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[C:26](=O)[O:27][C:28]2=[O:33].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:29](=[CH:30][CH:31]=[CH:32][C:24]=4[O:23][CH2:22][O:21][CH3:20])[C:28]3=[O:33])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1cccc2c1C(=O)OC2=O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCOc1cccc2c1C(=O)N(CC1OCCc3c1sc(N)c3C(=O)OC(C)(C)C)C2=O
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A mixture of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.15 g, 0.53 mmol) and 4-methoxymethoxy-isobenzofuran-1,3-dione (135 mg, 0.64 mmol) was dissolved in distilled acetonitrile (7 ml) under nitrogen. The flask was cooled in an ice bath with stirring and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g, 0.64 mmol), and triethylamine (0.22 ml, 1.59 mmol) were added. The reaction was warmed to ambient temperature and stirred for 18 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (40 ml). The organic layer was washed with 1% hydrochloric acid (2×10 ml), saturated sodium bicarbonate (10 ml), and brine (10 ml). The resulting solution was dried (Na2SO4), filtered, and the solvent evaporated in vacuo which afforded 0.18 g of a crude 2-amino-7-(4-methoxymethoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[CH3:21][O-:22].[Na+].CO>CC(O)=O>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:13])[C:3]=2[CH2:2][O:22][CH3:21])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:15][CH:16]=1
Reactant: O=c1c(CBr)c(-c2ccc(O)cc2)oc2ccccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCc1c(-c2ccc(O)cc2)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.52 g, 1.57 mmol), sodium methoxide (1.36 mL, 6.28 mmol, 25% in MeOH) and anhydrous MeOH (10 mL) was stirred overnight at rt. The reaction mixture was neutralized by addition of AcOH and the solvent was removed. The residue was poured into water and the solid was collected and purified by column chromatography (hexane:EtOAc 2:1) to give 155 mg of 2-(4-hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one (35.0%). MS (ES) m/z: 283.95 (M+1), 282.93 (M); Mp. 237-239° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:6][CH:7]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>O1CCCC1>[CH2:24]([N:27]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:6][CH:7]=1)[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3nc(CCl)co3)ncn2-c2ccccc2C1=O
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1coc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)n1
Yield: 67 %

Procedure:
0.30 g (0.00091 mol) of 3-(4-chloromethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 40 ml of tetrahydrofuran, treated with 2.5 ml (0.0183 mol) of dipropylamine and boiled at reflux for 20 hrs. The solution was completely freed from the solvents and the residue was chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent. There was obtained 0.24 g (67%) of 3-(4-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as a white solid. An analytical sample was recrystallized from diisopropyl ether and gave white crystals; m.p. 109°-110°.