Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].N>O1CCOCC1.O>[NH2:16][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: Cc1cc(Nc2cccc(N)c2)nc(N)n1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2cccc(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Temperature: 25 °C
Yield: 103.9 %

Procedure:
To a suspension of diamine E2 (5.25 g, 20.85 mmol) and dry pyridine (8.40 mL, 104.26 mmol) in dry dioxane (200 mL) was added 4-nitrobenzoyl chloride (10.79 g, 58.13 mmol), and the resulting solution was refluxed for ˜14 h. After this time, the reaction mixture was cooled to room temperature, and then basified by addition of aqueous ammonia solution. The resulting solution was diluted with H2O, and the resulting precipitate collected by filtration to afford amide E3 as an amorphous yellow-brown solid (7.89 g, 94%) [a small sample of this crude material was reprecipitated from acidified MeOH:EtOAc for characterisation, whilst the bulk was used without further purification]; 1H NMR (400 MHz, DMSO): δ 12.99 (br s, 1H, pyrimidinyl-N+—H), 10.82 (s, 1H, ArNHAr), 10.76 (br s, 1H, ArC(O)NHAr), 8.35 (dd, J=6.92, 1.99 Hz, 2H, ArH), 8.27 (d, J=6.92, 1.99 Hz, 2H, ArH), 7.90 (v v v br s, 2H, ArNH2), 8.20-7.50 (m, 4H, ArH & ArNH2), 7.45-7.10 (m, 2H, ArH), 6.25 (s, 1H, ArH), 2.28 (s, 3H, ArCH3); LCMS (APCl+): 365 (100%).
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)C(N)=O.[N+:10](=[CH2:12])=[N-].[C@@:13]12([OH:22])N(C)[C@@H:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]=[CH:14]2>C(OCC)C.CO.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[CH3:3][N:10]1[CH:12]2[CH2:19][CH:13]([OH:22])[CH2:14][CH:15]1[CH:16]1[CH:17]2[CH2:18]1
Reactant: C=[N+]=[N-]
Reactant: CN(N=O)C(N)=O
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: Cl[Pd]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: N#Cc1ccccc1
Solvent: CO
Product: CN1C2CC(O)CC1C1CC12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
35 mL (0.349 mol) of 40% aqueous KOH was covered with 100 mL diethyl ether and cooled in the ice bath, and 23.64 g (0.101 mol) of N-methyl-N-nitrosourea was added batchwise, then the mixture was stirred for 10 minutes. Then the ether phase was decanted off, again combined with diethyl ether, swirled around, and decanted off. The combined organic phases were dried over solid KOH while cooling with an ice bath and the solution obtained was further used. 25 mL of the diazomethane solution prepared above and then 53.4 mg (0.000139 mol) of bis(benzonitrile)dichloropalladium(II) was added to a solution of 4.01 g (0.028 mol) of tropenol in 25 mL diethyl ether and 5 mL of methanol while cooling with an ice bath. A further 8 mL of the diazomethane solution was added, then two lots of 10 mL of diazomethane solution, each after 30 minutes, and the mixture was then stirred for another 30 minutes. The solvent was concentrated by evaporation, extracted with hot hexane, filtered hot, evaporated to dryness. Yield: 4.25 g of slightly yellowish crystals (96% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])[CH3:42])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CNCCCN(C)C
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N(C)CCCN(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 72.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (20 mg, 0.04 mmol) in DCM (5 mL) was added N,N,N′-trimethyl-1,3-propanediamine (0.029 mL, 0.20 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (16 mg, 72%). LC-MS m/z 552 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.66 (m, 4H), 2.03 (m, 2H), 2.19 (s, 6H), 2.32 (s, 3H), 2.98 (s, 3H), 3.37 (m, 4H), 4.15 (s, 2H), 7.17 (t, 2H), 7.45 (d, 1H), 7.53 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])(C)C)(C)(C)C.C([Li])(CC)C.CN(C)[CH:24]=[O:25].[C:27](O)(=O)C>O1CCCC1.O>[Cl:16][C:10]1[C:9]([O:8][CH3:27])=[CH:14][CH:13]=[C:12]([Cl:15])[C:11]=1[CH:24]=[O:25]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1Cl
Reactant: CN(C)C=O
Reactant: CC(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)c(C=O)c1Cl
Temperature: -78 °C

Procedure:
Dissolve tert-Butyl-(2,4-dichloro-phenoxy)-dimethyl-silane (48.4 g, 175 mmol) in tetrahydrofuran (575ml) and cool to −78° C. Add sec-butyl lithium (1.4M, 131 ml, 183 mmol) slowly at −78° C. and stir at −78° C. for 30 minutes. Add N,N-dimethylformamide and stir at −78° C. for 1.5 hours. Pour reaction mixture into acetic acid in water (1:12, 830 ml) and stir warming to room temperature. Extract with ether, wash with water, brine dry over sodium sulfate, filter and concentrate to yield a mixture of the title compound and TBS protected analog. Slur in hexanes and filter to yield 15 g (45%) of 2,6-dichloro-3-hydroxy-benzaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7](O)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:18])=O>>[CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7]([Cl:18])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(N(C)C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(N(C)C)nc1Cl

Procedure:
A suspension of 16 g of 2-dimethylamino-4-hydroxy-5-carboethoxy-pyrimidine in 100 ml of phosphorus oxychloride is heated to the boil for half an hour whilst stirring and is then filtered hot, and the filtrate is evaporated under reduced pressure. 200 g of ice are added to the oily residue. 200 ml of methylene chloride are added and 30% strength sodium hydroxide solution is then added, whilst cooling with ice, until the pH reaches 8. Inorganic salts which have precipitated are then filtered off and rinsed with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and evaporated. 2-Dimethylamino-4-chloro-5-carboethoxypyrimidine is obtained as a yellowish oil which can be used further without purification.
Reaction SMILES: C(O)(=O)C.[C:5]([C:7](=[N:11][O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8]([NH2:10])=[NH:9])#[N:6].C(N(CC)CC)C.BrBr.[S-:27][C:28]#[N:29].[K+]>CO>[CH3:17][O:16][C:14]([CH2:13][O:12][N:11]=[C:7]([C:8]1[N:10]=[C:28]([NH2:29])[S:27][N:9]=1)[C:5]#[N:6])=[O:15]
Reactant: COC(=O)CON=C(C#N)C(=N)N
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)CON=C(C#N)c1nsc(N)n1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a suspension of 2-cyano-2-methoxycarbonylmethoxyiminoacetamidine acetate (495 g) in methanol (4.95 l) was dropped triethylamine (512.6 g) at -10° C. under stirring and cooling, and further, bromine (357.3 g) was added to the above mixture at the same temperature. After the reaction mixture was stirred for 15 minutes, a solution of potassium thiocyanate (216 g) in methanol (2.16 l) was dropped thereto at -10° to -5° C. under stirring, which was continued for 30 minutes at 0° to 5° C. The resulting precipitates were collected by filtration, washed with water (5 l) and dried to give 2-methoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetonitrile (syn isomer) (430 g), which was recrystallized from aqueous methanol, mp. 225° to 227° C. (dec.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]1=[O:19].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([N:15]2[CH2:16][CH2:17][CH2:18][C@@:11]3([C:10](=[O:19])[N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[Cl:2])[CH2:13][CH2:12]3)[CH2:14]2)=[N:22][CH:23]=1
Reactant: O=C1N(c2ccccc2Cl)CC[C@]12CCCNC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(N2CCC[C@]3(CCN(c4ccccc4Cl)C3=O)C2)nc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of (5S)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (40.0 mg, 0.000133 mol, prepared by using a procedure analogous to that used for the synthesis of example 92, steps 1-3), 2-chloro-5-nitropyridine (23 mg, 0.00015 mol), and potassium carbonate (55 mg, 0.00040 mol) in N,N-dimethylformamide (1.0 mL, 0.013 mol) was stirred at 120° C. for 1.5 hours. After cooling the reaction mixture to ambient temperature the solid was filtered off and the filtrate was concentrated in-vacuo to afford the desired product. LC-MS: 387.1 (M+H)+. The resulting residue was dissolved in methanol and to this solution was added platinum [5 wt. % (dry basis) on activated carbon, wet, Degussa type F101, RA/W (Aldrich #330159), 15 mg] under an atmosphere of H2 (g) at rt for 2 h. The catalyst was filtered off from the mixture and the filtrate was concentrated in-vacuo to afford the product in quantitative yield. LC-MS: 357.1 (M+H)+.
Reaction SMILES: C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28]O)[CH:24]=[CH:23][CH:22]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.C1COCC1>[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cccc(CCO)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
ADDP (49.0 g, 194.09 mmol) was added to a mixture of 2-(6-methoxypyridin-2-yl)ethanol (22.87 g, 149.30 mmol), phthalimide (24.16 g, 164.23 mmol), tributylphosphine (48.5 mL, 194.09 mmol) and THF (340 mL) at 0° C. under argon atmosphere to give a solution. The solution was stirred at room temperature for 16 hr, to the reaction mixture was added ethyl acetate (about 500 mL), and the mixture was stirred at 0° C. for 20 min. The insoluble substance was removed by filtration with ethyl acetate, and washed with ethyl acetate. The filtrate was poured into water (1000 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane), and the precipitate was collected by filtration with hexane to give 2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (29.03 g, 103 mmol, 69%) as an off-white powder.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1>[CH3:31][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
A solution of the product of Example 44, step C (85 mg, 0.189 mmol), trimethylboraxine (0.026 mL, 0.189 mmol), potassium carbonate (78 mg, 0.567 mmol) and tetrakis-(triphenylphosphine)palladium (21.8 mg, 0.0189 mmol) in water/1,4-dioxane (1:10, 0.55 mL) was heated to 110° C. for 5 h and then stirred at ambient temperature for 15 h. The reaction mixture was then filtered through a celite bed and concentrated in vacuo to afford the crude product which was then purified by column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to provide tert-butyl 6-methyl-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (43 mg, 53%): 1H NMR (CDCl3, 300 MHz) δ 7.98-7.94 (m, 3H), 7.63 (s, 1H), 7.54-7.46 (m, 3H), 4.56 (s, 2H), 3.83 (br s, 2H), 2.86 (br s, 2H), 2.51 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: FC(F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=O.[N+:14]([O-:17])(O)=[O:15].[Br:18][C:19]1C=C(O)[C:22]([O:25]C)=[CH:23][CH:24]=1>C(OCC)(=O)C.[Cl-].[Na+].O>[Br:18][C:19]1[CH:7]=[C:6]([O:5][CH3:3])[C:22]([OH:25])=[C:23]([N+:14]([O-:17])=[O:15])[CH:24]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(Br)cc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Br)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
Trifluoroacetic anhydride (3.50 ml) was cooled to −78° C. 61% nitric acid (1.85 ml) was slowly added dropwise at −78° C., and the resultant mixture was stirred at 0° C. for 2.5 hours. The above nitrating agent was added to a solution of 4-bromoguaiacol (5.00 g) in ethyl acetate (50 ml) and the mixture was stirred at 0° C. for 1.5 hours. Saturated brine was added to the reaction solution, and an organic layer was then separated. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, concentrated, and then allowed to cool to form crystals. After filtration, the crystal was washed with a small amount of n-hexane, and then dried under reduced pressure to obtain the object compound (4.02 g, yield 66%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=2[OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:24]=[O:25].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=2[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:17]1([CH3:23])[C:18]([CH:24]=[O:25])=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1
Reactant: C=O
Agent: O=C(O)c1cccc(-c2ccccc2)c1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccccc1C=O

Procedure:
To a mixture of 21.4 parts of 3-phenylsalicylic acid, 18.4 parts of toluene, 3.8 parts of 87% paraformaldehyde and 30 parts of acetic acid was added 2.0 parts of 95% sulfuric acid (catalyst). After being heated under reflux for 4 hours, the reaction mixture was washed with water, and unreacted toluene and water were removed by vacuum distillation to give 32 parts of 3-phenylsalicylic acid-toluene-formaldehyde co-condensation product. 10 parts of the co-condensation product was converted into its zinc salt in a similar manner as in Synthesis Example 4. There was obtained 10.8 parts of zinc salt of 3-phenylsalicylic acid-toluene-formaldehyde co-condensation product.
Reaction SMILES: [PH4+].[C:2]1([CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-:10].[K+].[K+].[CH:15](=O)/[CH:16]=C/C>O>[C:9]([O:10][CH2:15][CH3:16])(=[O:12])[CH2:3][CH2:4][CH:5]=[CH:6][CH:7]=[CH:2][CH3:8]
Reactant: O=C([O-])[O-]
Reactant: C/C=C/C=O
Reactant: Cc1ccccc1
Agent: [K+]
Agent: [PH4+]
Solvent: O
Product: CC=CC=CCCC(=O)OCC
Temperature: 65 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
Next, in a stream of nitrogen, the phosphonium salt (b) (420 g, 0.92 mol), toluene (1600 ml), potassium carbonate (506.2 g, 3.66 mol), and crotonaldehyde (256.7 g, 3.66 mol) were put into a 5-L flask, followed by stirring at 65° C. for 7 hours. The reaction solution was cooled to room temperature, and water (840 g) was put thereinto, followed by stirring for 30 minutes, and then subjected to separation of liquid. The solvent was evaporated from the organic layer under a reduced pressure. A solid thus precipitated was removed by filtration. This solution was distilled under a reduced pressure (65 to 70° C./1.5 torr), and ethyl 4,6-octadienoate (c) was obtained (114.4 g, yield 74%).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].OS(O[CH2:11][C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1)(=O)=O.[C:22](=[S:24])=[S:23].Cl>FC(F)(F)C(O)=O.[OH-].[Na+]>[N+:1]([C:17]1[CH:18]=[CH:19][C:20]2[CH2:21][C@H:12]3[CH2:11][S:24][C:22](=[S:23])[N:13]3[CH2:14][C:15]=2[CH:16]=1)([O-:4])=[O:2]
Reactant: O=S(=O)(O)OC[C@@H]1Cc2ccccc2CN1
Reactant: S=C=S
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)CN1C(=S)SC[C@@H]1C2
Temperature: 20 °C
Reaction time: 120 h

Procedure:
Finely powdered anhydrous sodium nitrate (85 g.) is added to a solution of (S)-3-hydroxysulphonyloxymethyl1,2,3,4-tetrahydroisoquinoline (122 g.) in trifluoroacetic acid (1,000 cc.). The reaction mixture is stirred for 5 days at a temperature of about 20° C. and is then evaporated under reduced pressure (25 mm. Hg, followed by 1 mm. Hg). The residue is washed with diethyl ether (3 × 200 cc.). The light yellow solid obtained is ground and then dried at 40° C. under reduced pressure (1 mm.Hg). The solid thus obtained is dissolved in 0.3N sodium hydroxide solution (5,000 cc.); carbon disulphide (35 cc.) is added to the solution obtained, whilst stirring, and the stirring is continued at a temperature of about 20° C. for 17 hours. The mixture is neutralised by adding 4N hydrochloric acid. The precipitate formed is filtered off, washed copiously with water and then with ethanol, dried under reduced pressure (0.1 mm. Hg) and then dissolved in boiling toluene (3,200 cc.). The insoluble matter is filtered off over Celite and the filtrate is cooled to about 10° C. The crystals which have appeared are filtered off, washed with ethanol (100 cc.), dried at 80° C. under reduced pressure (0.1 mm. Hg) and recrystallised from a mixture of acetonitrile and ethanol (1:1 by volume) (1,000 cc.). (S)-7-Nitro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (45 g.) melting at 182° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:6][CH:5]=1.[CH:19](O)=O>C(OC)(OC)OC>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:18])=[CH:9][CH:8]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]=[CH:19]1
Reactant: O=CO
Reactant: COC(=O)c1ccc(Nc2ccccc2N)cc1
Solvent: COC(OC)OC
Product: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A stirred solution of give 4-(2-aminophenylamino)benzoic acid methyl ester (13 g, 0.054 mol) in trimethyl orthoformate was treated with formic acid (13 mL), heated at reflux temperature for 1 h, cooled to room temperature and concentrated in vacuo. The residual oil was purified by column chromatography (silica, CHCl3/MeOH 1%) to give the title compound in 90% yield, 1H NMR (400 MHz, CDCl3): 8.26-8.28 (m, 3H), 8.17 (s, 1H), 7.90 (bs, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.59 (m, 1H), 7.40 (m, 1H), 7.26 (s, 1H). 3.9 (s, 3H). LCMS (ESI+) 253 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[C:12]([Cl:21])[CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:12]1[CH:11]=[C:10]([NH:9][C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1])[CH:20]=[CH:19][C:13]=1[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: CN(C)C(=O)c1ccc(N)cc1Cl
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(NC(=O)C(C)(C)CCl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloro-2,2-dimethylpropionyl chloride (1.86 g) was added dropwise over 5 minutes to 4-amino-2-chloro-N,N-dimethylbenzamide (2.00 g) suspended in dry methylene chloride (40 ml) and dry triethylamine (1.21 g) with stirring, keeping the temperature below 10° C. After stirring for 1 hour and warming to room temperature, methylene chloride (40 ml) was added and the solution washed with 2M hydrochloric acid, saturated aqueous sodium bicarbonate and then saturated brine. The solution was then dried and evaporated to yield a sticky yellow solid which was recrystallised from ethyl acetate/chloroform to give 2-chloro-4-(3'-chloro-2',2'-dimethylpropionamido)-N,N-dimethylbenzamide, as a white crystalline solid (2.349 g) m.p. 179°-181° C.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[H-].[Na+].Br[CH:15]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][N:21]2[S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:16]>CN(C=O)C>[S:26]([N:21]1[C:22]2[C:18](=[C:17]([CH:15]([N:2]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])[CH3:16])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1)([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=1)(=[O:27])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)Br)cccc32)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)N4C(=O)c5ccccc5C4=O)cccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 112.5 %

Procedure:
To a solution of isoindoline-1,3-dione (3.83 g, 20.0 mmol), in dry DMF (70 mL) at 0° C. under argon was added NaH (1.04 g, 26 mmol). The resultant mixture was stirred at RT for 30 min. A solution of 284 (9.8 g, 26 mmol) in dry DMF (30 mL) was added and the mixture was stirred at RT for 4 h. The mixture was concentrated in vacuo and purified by SiO2 chromatography to afford 10 g (86%) of 2-(1-(1-tosyl-1H-indol-4-yl)ethyl)isoindoline-1,3-dione (286) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.87-7.81 (m, 8H), 7.48 (d, J=7.6 Hz, 1H), 7.38-7.33 (m, 3H), 6.82 (d, J=3.6 Hz, 1H), 5.77-5.74 (m, 1H), 2.29 (s, 3H), 1.84 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].S(=O)(=O)(O)O.[CH3:17]O>>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:17])=[O:6])[CH3:2]
Reactant: CCc1ccccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1ccccc1C(=O)OC
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of 11.8 g. (0.076 mole) of 2-ethylbenzoic acid in 25 ml. of absolute methanol is treated cautiously with 2.5 ml. of concentrated sulfuric acid and heated to reflux. After 4 hours, the mixture is poured onto ice and the oily product is extracted into ether. Evaporation of the washed (water, 5% aqueous sodium bicarbonate and water) and dried extract under reduced pressure leaves methyl 2-ethylbenzoate as the residual colorless oil in a yield of 86%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1CSCCN1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCSCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, thiomorpholine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.60 minutes; C20H18C12N4O2S (449.36); mass spectrum: (M+H)+=449.1.