Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[I:11].[Br:13]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5]([I:11])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][Br:13]
Reactant: COC(=O)c1c(C)cccc1I
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(I)cccc1CBr

Procedure:
A mixture of 2-iodo-6-methyl-benzoic acid methyl ester (3.59 g, 13 mmol), N-bromosuccinamide (2.3 g, 13 mmol), and benzoyl peroxide (0.056 g, 0.21 mmol) in carbon tetrachloride (20 mL) was heated at reflux until the starting materials were mostly consumed. Workup afforded 2-bromomethyl-6-iodo-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]12[O:16][CH:12]([CH2:13][NH:14][CH2:15]1)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[N+:1]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]1[O:16][CH:5]2[CH2:15][NH:14][CH2:13]1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)C1CNCC2O1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)C1CNCC2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Concentrated nitric acid (10 mL) was added to a mixture of 12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (5.1 g, 32 mmol) and concentrated sulfuric acid (10 mL) at 0° C. The resulting solution was stirred at 0° C. for 30 min before pouring onto ice, adding 10 N NaOH slowly until basic, and extracting with CH2Cl2 (2×25 mL). The combined organic layers were dried over MgSO4, filtered, concentrated and purified with silica gel chromatography (0-30% MeOH in CH2Cl2) to obtain 4-Nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a gummy, brown oil (4.2 g, 65%). MS (m/e) 207 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)c1ccccc1n2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a stirred solution of carbazole (20.0 gm, 0.119 moles) in dry chloroform (300 ml) at 0° C., D-10 camphor sulphonic acid (5% W/W, 1.0 gm) was added followed by a solution of 3,4-dihydro 2H-pyran (0.149 moles, 13.6 ml) in dry chloroform (50 ml) dropwise over a period of 30 min. The reaction mixture was gradually warmed to room temperature and stirred at the same temperature for 2 hours. The reaction mixture was diluted with chloroform (400 ml) and washed with a solution of saturated NaHCO3 (150 ml), followed by water (150 ml), dried over Na2SO4 and concentrated to give 31 gm of crude material which was recrystallised from 500 ml of iso-propanol to give 24 gm of the title product as white crystalline powder, m. p: 131-133° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13]C[N:11]([S:15]([C:18]2[C:19]3[C:20]([Br:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33]C(N[C@H]1CCN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:11]([S:15]([C:18]2[C:19]3[C:20]([Br:28])=[CH:21][N:22]=[C:23]([O:33][CH3:29])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Product: COc1ncc(Br)c2c(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)cccc12

Procedure:
3-(tert-Butoxycarbonylamino)-1-(2-oxy-4-bromo-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 3) can be obtained by using Intermediate 1 in the method of Example 6-1, Step A instead of Intermediate 1a, and then used in the method of Step B to obtain 3-(tert-butoxycarbonylamino)-1-(4-bromo-1-methoxy-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 4), and then Intermediate 4 can be used in the method of Step C to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27]C)=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][NH:15][C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:25]([OH:27])=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][N:15]([CH3:32])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(c2ccccc2)n2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-benzyloxy-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (28 mg, 0.074 mmol) in anhydrous DMF under inert atmosphere was added sodium hydride (3 mg, 0.111 mmol, 95% dispersion in oil). The mixture was treated with iodomethane (6 μL, 0.089 mmol) and stirred at room temperature for 1 hour. When the methylation was complete, several drops of H2O were added and the mixture stirred at room temperature for 1 hour. The mixture was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions yielded the title product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 12.90 (s, 1H), 7.51-7.49 (m, 2H), 7.39-7.31 (m, 6H), 7.01-7.00 (m, 2H), 5.80 (s, 1H), 5.27 (dd, J=11.2, 25.2 Hz, 2H), 4.21 (d, J=4.8 hz, 1H), 4.18 (d, J=4.4 Hz, 1H), 2.92 (s, 3H); ES MS (M+1)=378.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([Cl:15])=[CH:7][C:6]=1[Cl:16].[Li+].[OH-].O>C1COCC1>[Cl:16][C:6]1[CH:7]=[C:8]([Cl:15])[CH:9]=[C:10]([C:11]([F:13])([F:14])[F:12])[C:5]=1[CH2:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)Cc1c(Cl)cc(Cl)cc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1c(Cl)cc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2,4-dichloro-6-trifluoromethylphenylacetic acid methyl ester (0.93 mmol) in 3 mL THF was added an aq. solution of LiOH (2.8 mmol, 2M). After stirring at RT for 3 days, water was added and the mixture was extracted twice with EtOAc. The aqueous phase was acidified to pH 2-3 with 1N HCl solution and extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as white solid.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:18][C:14]1[C:15]([OH:17])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CNCCc2cc(O)c(Br)cc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.655 g, 1.89 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20° C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.460 g of a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 1H), 6.65 (s, 1H), 2.90 (m, 1H), 2.73 (m, 5H), 2.55 (m, 1H), 1.19 (d, J=7 Hz, 3H). MS calculated for C11H14BrNO+H: 256, observed: 256.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][NH:17][C:18]3=[O:23])=[C:4]([O:31]C)[C:3]=1[F:33].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:29])([CH3:30])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:25])[F:26])[CH:11]2[NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][NH:17][C:18]3=[O:23])=[C:4]([OH:31])[C:3]=1[F:33]
Reactant: COc1c(C(C)(C)CC(O)(C=Nc2cccc3c(=O)[nH]ccc23)C(F)(F)F)ccc(Cl)c1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2cc(Cl)c(F)c(O)c21
Temperature: 25 °C
Yield: 31.5 %

Procedure:
80.3 mg (0.166 mmol) of (rac.) 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one is mixed at room temperature with 1.7 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for two and one-half hours at room temperature. The reaction mixture is mixed with ice, and then saturated sodium bicarbonate solution is added in drops (pH 8). After ethyl acetate is added, and after ten minutes of vigorous stirring at room temperature, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water and with brine, dried, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 24.6 mg (31.6%) of the desired compound is isolated.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]([NH:17][C:18](=[O:25])[CH2:19][C:20](OCC)=[O:21])[NH:14][N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>N.CO>[CH3:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]3[N:17]=[C:18]([OH:25])[CH:19]=[C:20]([OH:21])[N:14]3[N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2nc3ccccc3nc2C)n[nH]1
Agent: N
Solvent: CO
Product: Cc1nc2ccccc2nc1-c1cc2nc(O)cc(O)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Method A (free form): A suspension of ethyl 3-{[3-(3-methylquinoxalin-2-yl)-1H-pyrazol-5-yl]amino}-3-oxopropanoate (20.0 g, 58.9 mmol) in 28% aqueous ammonia (295 mL) and methanol (1176 mL) was stirred overnight at room temperature, and then concentrated in vacuo. The residue was diluted with water (1500 mL) and ethyl acetate (1000 mL). The aqueous layer was concentrated in vacuo, and water (40 mL) was added. The mixture was acidified to pH 5-6 with 10% aqueous hydrochloric acid, and then ethanol (360 mL) was added. The resulting precipitate was collected and washed with 95% aqueous ethanol and ethanol to give 2-(3-methylquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol. MS (ESI): m/z 292 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:15]([CH2:16][CH2:17][C:18]#[N:19])=[CH:14][C:13]([CH2:20][OH:21])=[CH:12][N:11]=1.N1C=CN=C1.[C:27]([Si:31]([CH3:34])([CH3:33])Cl)([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>CN(C=O)C>[Si:31]([O:21][CH2:20][C:13]1[CH:14]=[C:15]([CH2:16][CH2:17][C:18]#[N:19])[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[N:11][CH:12]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:34])[CH3:33]
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2CCC#N)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2CCC#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 3-(2-(2-fluoro-5-methoxyphenyl)-5-(hydroxymethyl)pyridin-3-yl)propanenitrile (424 mg) and imidazole (155 mg) in DMF (10 mL) was added tert-butyldimethylchlorosilane (265 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (524 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.N#N.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][N:29]=[CH:28][C:27]=2[CH:31]=1.C([O-])(O)=O.[Na+]>ClCCl>[O:30]1[C:26]2[CH:25]=[CH:24][C:23]([NH:22][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:31][C:27]=2[CH:28]=[N:29]1
Reactant: Nc1ccc2oncc2c1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3oncc3c2)cc1
Yield: 72 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (171 mg, 0.783 mmol) in dichloromethane (4 mL).was added pyridine (150 μL, 1.86 mmol) and the mixture was stirred under. N2 for 5 min, after which time 5-amino-1,2-benzisoxazole (100 mg, 0.746 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (170 mg, 72%), single spot at Rf 0.68 (1:1 hexane:ethyl acetate). mp 130.0-130.6° C., HPLC purity 99+% (tR 2.44 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.62 (1H, d, J=1.0 Hz), 7.60 (2H, d, J=8.4 Hz), 7.48 (2H, m), 7.19 (3H, m), 6.86 (1H, s, N−H), 2.58 (2H, t, J=7.5 Hz), 1.58 (2H, sextet, J=7.4 Hz), 0.88 (3H, t, J=7.4 Hz). LCMS: 315.14 (M−). FAB-MS (MH+, C16H16N2O3S): calcd 317.0960, found 317.0962.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CS(C)=O>[CH3:46][O:45][C:43](=[O:44])[CH2:42][O:26][C:23]1[CH:24]=[C:25]2[C:20]([C:19]([C:27](=[O:28])[NH2:29])=[CH:18][N:17]2[CH2:16][C:15]([N:10]2[CH2:11][C@H:12]([F:14])[CH2:13][C@H:9]2[C:7](=[O:8])[NH:6][CH2:5][C:4]2[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[C:3]=2[F:34])=[O:30])=[CH:21][CH:22]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)COc1ccc2c(C(N)=O)cn(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-6-hydroxy-1H-indole-3-carboxylic acid amide Example 578 (140 mg, 0.285 mmol) in DMSO (3 mL) was treated with Cs2CO3 (0.28 g, 0.85 mmol). The mixture was stirred at RT for 5 min, followed by addition of methyl 2-bromoacetate (0.039 mL, 0.428 mmol) and stirring at RT for 4 h. The mixture was partitioned between water and CH2Cl2, and the organic phase was washed twice with brine (the combined aqueous washings were filtered and the solid thus obtained was dried in vacuo to give an aliquot of the title compound), dried (phase separator) and concentrated under reduced pressure. Purification by preparative HPLC (SunFire C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) afforded after lyophilization of the purified fractions the title compound as a white solid. MS: 563 [M+H]+; tR (HPLC conditions c): 4.17 min.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=O)=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[CH3:14][O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8](/[CH:12]=[CH:17]/[C:16]([O:15][CH3:14])=[O:37])[CH:7]=2)[C:3](/[CH:1]=[CH:17]/[C:16]([O:15][CH3:14])=[O:37])=[CH:4]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2c(C=O)c[nH]c2c1
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc2c(/C=C/C(=O)OC)c[nH]c2c1
Yield: 72.8 %

Procedure:
A mixture of 3,6-diformylindole (1 g), methyl(triphenylphosphoranylidene)acetate (7.76 g) and dry dioxane (50 ml) was stirred and heated under reflux for 6 hr under an atmosphere of nitrogen. The solvent was evaporated, the residue extracted with several portions of ether, the ether extracts evaporated and the crude product purified by flash chromatography, eluting with 2:3 ethyl acetate:hexane, to give dimethyl E,E-indole-3,6-diacrylate (1.2 g, 73%) as a yellow solid; partial NMR (250 MHz, DMSO-d6): 3.71(s, 3H, OCH3), 3.73(s, 3H, OCH3), 6.40(d, J=16.0 Hz, 1H, olefinic H); 6.60(d, J=16.0 Hz, 1H, olefinic H); 12.02(br s, 1H, NH).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: C1CCNC1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CN4CCCC4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with pyrrolidine. 1H-NMR (DMSO-D6) δ: 1.74 (m, 4H, CH2), 2.58 (m, 4H, CH2), 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.20 (s, 2H, CH2), 7.04 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.55 (d, 2H, J=8.8 Hz, Ph-H), 7.66 (d, 2H, J=8.8 Hz, Ph-H), 8.48 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.55 (s, 1H, NH), 9.58 (s, 1H, NH). MS (ESI+) m/z 406.97 [M+H]+ (C21H24N6OS requires 408.52).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:15])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[CH3:5].Cl.[C:18]([NH2:23])(=[NH:22])[CH:19]([CH3:21])[CH3:20].CN(C)C(N(C)C)=N>CN(C=O)C.O>[CH:19]([C:18]1[NH:22][CH:2]=[C:3]([C:4]([CH3:15])([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[CH3:5])[N:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C(=O)CBr)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)C(=N)N
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)c[nH]1
Yield: 29.7 %

Procedure:
A solution of 1-bromo-3-methyl-3-(3-nitro-phenyl)-butan-2-one (2.28 g, 8.0 mmol), isobutyramidine hydrochloride (3.58 g, 23.7 mmol) and 1,1,3,3-tetramethylguanidine (2.4 mL, 19.1 mmol) in DMF (10 mL) was heated at reflux for 24 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to afford 2-isopropyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.65 g, 30%) as a cream-coloured solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][N:3]=1.CN(C=O)C.N1C=CN=C1.[CH3:19][CH:20]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH3:21]>CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:21])[CH3:19])=[N:4][N:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1nnc(Br)s1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCc1nnc(Br)s1)(C(C)C)C(C)C
Reaction time: 5 h
Yield: 98.1 %

Procedure:
A 500 mL (one neck) round-bottom flask with a stir bar, septum and needle inlet was charged with (5-bromo-[1,3,4]thiadiazol-2-yl)-methanol (25 g, 128 mmol), DMF (250 mL), imidazole (17.9 g, 263 mmol, 2 equiv.) and TIPSCl (30.0 g, 155 mmol, 1.2 equiv.). The solution was stirred for 5 hours and diluted with EtOAc. The solution was washed with HCl (1N, 2×) and brine. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (0-10% EtOAc/Hex) to provide 2-bromo-5-triisoproylsilanyloxymethyl-[1,3,4]thiadiazole (44.1 g, 98%).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].Cl.[N+:6]([C:9]1[CH:18]=[CH:17][C:12]([NH:13][CH2:14][CH2:15][NH2:16])=[C:11]([CH3:19])[CH:10]=1)([O-:8])=[O:7]>O>[N+:6]([C:9]1[CH:18]=[CH:17][C:12]([NH:13][CH2:14][CH2:15][NH:16][C:2]([NH2:1])=[O:3])=[C:11]([CH3:19])[CH:10]=1)([O-:8])=[O:7]
Reactant: [N-]=C=O
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCN
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCNC(N)=O
Yield: 80.6 %

Procedure:
24.3 g (0.3 mole) of potassium isocyanate in solution in 75 cm3 of water is added to 57.9g (0.25 mole) of 4-nitro-2-methyl-N-(β-aminoethyl) aniline monohydrochloride in 235 cm3 of water at 60°. After keeping the reaction mixture for 15 minutes in a boiling water bath, drying yields 48 g of 4-nitro-2-methyl-N-(β-ureido-ethyl)aniline which, after recrystallization in acetic acid, melts at 186° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH:13]1([NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[CH2:15][CH2:14]1>>[CH:13]1([NH:16][C:17]([C:18]2[CH:23]=[C:22]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][CH:10]=[CH:11][N:12]=4)=[CH:4][CH:3]=3)[C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:34])[CH2:14][CH2:15]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2ncc[nH]2)cc1

Procedure:
Example 8 was prepared using 2-(4-bromophenyl)-1H-imidazole and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:14]=[CH:15][C:16]3[C:21]([C:5]=2[S:4]1(=[O:23])=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:2].[C:24](Cl)([Cl:26])=[O:25]>>[CH2:1]([N:3]1[C:8]([C:24]([Cl:26])=[O:25])=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:14]=[CH:15][C:16]3[C:21]([C:5]=2[S:4]1(=[O:23])=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCN1C=C(N2CCCC2)c2ccc3ccccc3c2S1(=O)=O
Product: CCN1C(C(=O)Cl)=C(N2CCCC2)c2ccc3ccccc3c2S1(=O)=O

Procedure:
2-Ethyl-4-(1-pyrrolidyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide was prepared analogous to Example 55b from 2-ethyl-4-(1-pyrrolidyl)-2H-naphtho[2,1-e]-1,2-thiazine-1,1-dioxide and phosgene and recovered in the form of a solution in tetrahydrofuran.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=1[S:24]([O:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(=[O:26])=[O:25]>C1C=CC=CC=1>[C:8]1([NH:14][N:15]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][O:27][S:24]([C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:17][CH3:16])(=[O:26])=[O:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccccc1S(=O)(=O)OCC(=O)c1ccccc1
Reactant: NNc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: COc1ccccc1S(=O)(=O)OCC(=NNc1ccccc1)c1ccccc1

Procedure:
Into a reactor, equipped with a Dean-Stark separator, were introduced 100 ml of benzene, 1 ml of acetic anhydride, 10.8g (0.1 mol) of phenylhydrazine and 30.6 g (0.1 mol) of 3-methoxy-4-benzenesulphonyloxy-acetophenone. The reaction medium was stired and refluxed for 1 hour.