Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH3:9])C)C.[H-].[Na+].CO[C:17](=[O:28])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=1.Cl>O1CCCC1>[OH:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH2:9][C:22]([C:21]1[CH:20]=[CH:19][C:18]([C:17](=[O:28])[CH2:9][C:8](=[O:10])[C:7]([CH3:11])([OH:6])[CH3:12])=[CH:27][CH:26]=1)=[O:24]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCOC(C)OC(C)(C)C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)CC(=O)c1ccc(C(=O)CC(=O)C(C)(C)O)cc1
Reaction time: 7 h
Yield: 49 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 9.9 gm (57 mmol) of above-mentioned 3-(1-ethoxyethoxy)-3-methyl-butane-2-one, 2.3 gm (57 mmol) of 60% sodium hydride, 5.0 gm (25 mmol) of dimethylterephthalate and 50 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and the refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N hydrochloric acid was added and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The reaction mixture was stirred at room temperature while adding 30 ml of methnol with ten drops of 2N hydrochloric acid. A mixed solvent of acetone-chloroform was added to the crude product, and recrystallization afforded 4.1 gm of the title compound as pale yellow crystals (yield: 48%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=[O:17])[CH2:14][CH2:15][S:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.BrC1C=CC=CC=1.[Mg].[Cl-].[NH4+]>C(OCC)C>[OH:17][C:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]2[CH:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[S:16][CH2:15][CH2:14]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCSC2CN(Cc3ccccc3)CC12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Brc1ccccc1
Product: OC1(c2ccccc2)CCSC2CN(Cc3ccccc3)CC21
Reaction time: 3 h

Procedure:
A solution of 21.15 g of (4aRS,7aSR)6-benzyl-4-oxoperhydrothiopyrano[2,3-c]pyrrole in 150 cm3 of anhydrous ethyl ether are added over 30 minutes to a solution of phenylmagnesium bromide prepared from 19.8 cm3 of bromobenzene and 4.52 g of dry magnesium in 120 cm3 of anhydrous ethyl ether. The reaction mixture is stirred at the reflux temperature for 3 hours, and then for 20 hours at 20° C. The mixture, to which 200 cm3 of ethyl ether has been added, is stirred with 600 cm3 of a saturated aqueous solution of ammonium chloride. The aqueous phase is extracted with 200 cm3 of ethyl ether, the two pooled etherial extracts are washed twice with 300 cm3 of a saturated aqueous solution of sodium chloride and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (5.4 kPa) at 35° C. 12.2 g of (4RS,4aSR,7aRS)-4-hydroxy-4-phenyl6-benzylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid; melting point 137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH2:12].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>O=P(Cl)(Cl)Cl>[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]2[NH:12][C:3]3[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nc3ccc(C(F)(F)F)cc3[nH]2)cc1

Procedure:
2-(4-Nitrophenyl)-5-trifluoromethyl benzimidazole was synthesized as follows: 1,2-diamino-4-trifluoromethylbenzene (1.76 g, 10.0 mmole) was mixed with 4-nitrobenzoic acid (1.67 g, 9.8 mmole), dissolved in POCl3 (12 ml), and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice. The resulting solid was filtered, washed with NaHCO3 and used without further purification.
Reaction SMILES: C([C:4]1([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)C#C.N(C(C)(C)C#N)=N[C:17](C)([CH3:20])[C:18]#N.[CH2:27]([SnH:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>>[CH2:36]([Sn:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:20]/[CH:17]=[CH:18]/[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[CH2:37][CH2:38][CH3:39]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: C#CCC1(O[Si](C)(C)C)CCCCC1
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCC[Sn](C/C=C/C1CCCCC1O[Si](C)(C)C)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To a stirred mixture of 31/5 g of 1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg of azobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. The stirred mixture is heated to about 80° C. The initial exothermic reaction is moderated, and the temperature is subsequently maintained at 130°-135° C. for one hour.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[O:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:16]1=2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:16]2[O:15][CH2:20][CH2:19][O:18][C:17]=2[CH:21]=1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc4c(c3)OCCO4)cc12
Temperature: 100 °C
Yield: 10.2 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (40.0 mg, 0.14 mmol), (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (27.4 mg, 0.152 mmol) and 2 N aqueous potassium carbonate solution (0.2 mL, 0.4 mmol) in toluene (0.3 mL) and EtOH (0.7 mL) was purged with N2, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under N2. The reaction mixture was heated to 100° C. for 48 hours, cooled to room temperature and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 10.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to afford the title compound (4.7 mg, 10% yield). MS (ES+) 331.1 (M+H)+. Retention time=2.62 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:50])([F:49])[C:22]1[CH:23]=[C:24]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:25][N:26]([CH:30]1[CH2:36][CH2:35][CH2:34][NH:33][C:32]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:31]1=2)[C:27](=[O:29])[CH3:28].N1C=CC=CC=1>C(Cl)Cl>[CH:5]1([O:10][C:1]([N:33]2[CH2:34][CH2:35][CH2:36][CH:30]([N:26]([C:27](=[O:29])[CH3:28])[CH2:25][C:24]3[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:22]([C:21]([F:20])([F:49])[F:50])[CH:23]=3)[C:31]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:32]2=3)=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: OC1CCCC1
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(Cl)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC2CCCC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Add phosgene (0.5 mmol) to a solution of cyclopentanol (0.5 mmol) in DCM (1 mL) at 0° C. under nitrogen. To this cooled solution add diisopropyl ethylamine (0.5 mmol) dropwise. After stirring for 1 h with cooling, warm the mixture to room temperature and add N-(3,5-Bis-trifluoromethyl-benzyl)-N-(8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.05 g, 0.11 mmol) in dichloromethane (0.5 mL) and pyridine (0.5 mmol). After stirring at room temperature for 14-16 h dilute the reaction with dichloromethane (2 mL) and wash with 5% HCl (2 mL) followed by water (2 mL) and brine (2 mL). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the crude mixture over silica gel using ethyl acetate/hexane (10-30%) to elute. This affords the title compound (0.06 g, 95%) as an oil which crystallizes upon standing: MS (ES+): 577 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=1.C(N(CC)CC)C.CN1C(=O)CCC1>O>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2nnc(N3CCNCC3)c3ccccc23)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 180 °C
Yield: 70 %

Procedure:
1-Benzyl-4-piperazin-1-yl-phthalazine (500 mg, 1.64 mmol) and 2-chloro-5-nitropyridine are combined in a 10 mL microwave vial. Triethylamine (2.96 mL, 2.14 mmol) and NMP (4.8 mL) are added. The vial is sealed and heated to 180° C. for 15 min. The crude reaction mixture is poured into water and the resulting precipitate is isolated by filtration to afford the title compound (500 mg, 70% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1cc(Br)cc(C#N)c1OC
Reactant: OB(O)c1ccco1
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: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccco2)cc(C#N)c1OC
Temperature: 85 °C
Yield: 92.7 %

Procedure:
To a mixture of 5-bromo-2,3-dimethoxybenzonitrile (0.958 g, 4.0 mmol), 2-furylboronic acid (0.53 g, 4.7 mmol), dioxane (24 mL), H2O (8 mL) and Na2CO3 (1.1 g, 10.4 mmol) was added tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol). The mixture was degassed by alternately putting under house vacuum and argon three times for several minutes each then heated at 85° C. under argon for 16.5 hrs. After cooling to room temperature, the mixture was diluted with H2O and extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-20% EtOAc-hexanes) provided 5-(furan-2-yl)-2,3-dimethoxybenzonitrile as a white solid (0.85 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[N:17]1([CH2:22][CH2:23][C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=[CH:18]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:24](=[O:25])[CH2:23][CH2:22][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[C:4]=2[CH:3]=1
Reactant: O=S1c2ccccc2Nc2cc(Cl)ccc21
Reactant: O=C(O)CCn1ccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CCn1ccnc1)N1c2ccccc2S(=O)c2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
A mixture of 25 g of 2-chloro-phenothiazine-5-oxide, 14 g of 3-(imidazol-1-yl)-propionic acid, 20.6 g of dicyclohexylcarbodiimide and 250 ml of tetrahydrofuran is stirred for 1 hour at 0° and then for 2 hours at 30°. It is worked up in the customary manner to give 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine-5-oxide, melting point 148°-149°.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[Cl:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O>[Cl:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:10]=1[CH2:11][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[S:2](=[O:4])(=[O:3])[NH:5][C:6]1=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Fc1cccc(Cl)c1CNc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: O=C1NS(=O)(=O)c2ccccc2N1Cc1c(F)cccc1Cl
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
A solution of chlorosulfonylisocyanate (5.04 mL, 57.9 mmol) in nitroethane (100 mL) was cooled to approximately −40° C. and a solution of N-(2-chloro-6-fluorobenzyl)aniline (10.5 g, 44.6 mmol) in nitroethane (80 mL) added dropwise over approximately 10 min. The mixture was stirred at −40° C. for 10 min, then rt for 1 h, before the addition of further chlorosulfonylisocyanate (1.94 mL, 22.3 mmol) and stirring for 30 min at rt. Aluminium chloride (8.32 g, 62.4 mmol) was added and the mixture heated at reflux for 30 min, before cooling to rt and cautious addition to stirred ice-H2O (approximately 300 mL). After stirring for 15 min, the title compound (11.8 g, 34.6 mmol) was isolated by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][CH2:33][CH:34]([F:36])[F:35])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18]CC)=[O:17])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][CH2:33][CH:34]([F:35])[F:36])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(C(C)NC(=O)OC(C)(C)C)[nH]3)c2nc1NCC(F)F
Temperature: 110 °C

Procedure:
A glass microwave reaction vessel was charged with ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (950 mg, 1.887 mmol) and LiOH monohydrate (396 mg, 9.43 mmol) in dioxane (8.0 mL) and water (4.00 mL). The reaction mixture was stirred and heated in at 110° C. for 80 min. LC-MS indicated >87% conversion to the desired carboxylic acid m/z (ESI, +ve ion) 476.1 (M+H)+. The reaction mixture was transferred to a 250 mL RBF, using MeOH and concentrated to dryness affording 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid as an orange solid. The orange solid was treated with 4.0 M HCl solution in 1,4-dioxane (11.79 mL, 47.2 mmol) at RT and stirred for 30 min. The reaction mixture was concentrated to give 2-(1-aminoethyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (382b) as a red-orange solid. It was used in the subsequent step without further purification assuming quantitative yield. 19F NMR (377 MHz, DMSO-d6) δ ppm −120.68 (1F, s). (m/z (ESI, +ve ion) 376.1 (M+H)+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:8][CH:9]=1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc3c(c2)-c2cc(Cl)c4cccnc4c2NS3(=O)=O)CC1
Yield: 28.1 %

Procedure:
In a similar fashion using route 51 general procedure 118, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (100 mg, 0.3 mmol), 1-methyl piperazine (59 mg, 0.6 mmol) and NMP (2 ml) gave title compound (35 mg, 28%) after purification by column chromatography using DCM/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.CN(CCN(C)C)C.[CH2:27]([NH:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[CH3:28].[CH2:39]([Si:42]([CH3:45])([CH3:44])Cl)[CH:40]=[CH2:41]>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Si:42]([CH3:45])([CH3:44])[CH2:39][CH:40]=[CH2:41])[C:31]=1[C:30]([NH:29][CH2:27][CH3:28])=[O:38]
Reactant: C=CC[Si](C)(C)Cl
Reactant: CCNC(=O)c1ccccc1Cl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C=CC[Si](C)(C)c1cccc(Cl)c1C(=O)NCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (10.5 mL, 13.6 mmol) was added dropwise to a dry-ice/acetone cooled solution of TMEDA (1.0 mL, 6.5 mmol) in THF (10 mL), followed by the dropwise addition of a solution of the compound of example f (1.0 g, 5.45 mmol) in THF (10 mL). The reaction mixture was stirred at -78° C. for 30 min, then allyldimethylchlorosilane (10.9 mmol) was added and the mixture was stirred for 2.5 h at -78° C. The resulting reaction was warmed to -30° C., quenched with dilute aq citric acid, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 1:19 EtOAc/cyclohexane to give the desired compound as a white solid. m.p. 61-63° C.
Reaction SMILES: C(O[C:6]([C@@H:8]1[CH2:12][C@H:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[CH:31]=C[CH:29]=[CH:28][CH:27]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:32](=[O:44])[NH:33][C@:34]1([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:7])(C)(C)C.[CH2:45]([SiH](CC)CC)C.[C:52]([O:56][C:57]([NH:59]/[N:60]=[CH:61]/[CH2:62][CH2:63][CH2:64][CH2:65][CH:66]=[CH2:67])=[O:58])([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:42]([O:41][C:39]([C@@:34]1([NH:33][C:32]([C@@H:9]2[CH2:10][C@@H:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:45][CH:31]=4)[CH:15]=3)[CH2:12][C@H:8]2[C:6]([N:60]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH:66]=[CH2:67])[NH:59][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:58])=[O:7])=[O:44])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:40])[CH3:43]
Reactant: C=CCCCC/C=N/NC(=O)OC(C)(C)C
Reactant: CC[SiH](CC)CC
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Scaffold molecule 35 (135 mg, 0.225 mmol) and triethylsilane (71 μL, 0.447 mmol) was dissolved in DCM (2 mL) after which trifluoroacetic acid (TFA) (2 mL) was added. The mixture was stirred for 2 h and thereafter co-evaporated with toluene in order to remove the TFA. The residue was dissolved in DMF (3 mL) and 47 (60 mg, 0.263 mmol) and DIEA (118 μL, 0.677 mmol) were added. The temperature was lowered to 0° C. and the coupling reagent O-(7-azabenzotriazol-1-yl)-NNN′,N′-tetramethyluronium hexafluorophosphate (HATU) (94 mg, 0.247 mmol) was added. The cold solution was allowed to stir for half an hour and then for additional 16 h in room temperature. The solvent was removed by heating the reaction flask in a water bath under diminished pressure. The residue was thereafter dissolved in ethyl acetate and the organic phase washed three times with brine, dried, filtered and evaporated. Purification by HPLC (MeOH/H2O 90:10 with 0.2% triethylamine) gave 48 (140 mg, 82%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:20][NH:21]C(=O)OC(C)(C)C)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.[ClH:29]>O1CCOCC1>[Cl-:29].[NH2:21][CH2:20][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[NH+:17][CH:18]=[CH:19][N:9]12
Reactant: CC(C)(C)OC(=O)NCC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Reactant: Cl
Solvent: C1COCCO1
Product: NCC1(c2ccc(Br)cc2)c2ccccc2-c2[nH+]ccn21
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl {[5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindol-5-yl]methyl}carbamate (575 mg) in dioxane (2 mL) was added a HCl solution (3.265 mL, 4 M in dioxane) and stirred at room temperature for 1.5 h. After this time 1.5 mL more HCl solution was added and stirring continued for another 3 h. The reaction mixture was then concentrated (azeotroped once from toluene) and dried under vacuum to give title compound as a white solid. Mass. found (M+H)+, 342.0.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])=[CH:27][CH:28]=1)[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)CC(=O)OC
Reactant: O=C(c1ccc(CCl)cc1)N1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium tert-butoxide (1.4 g) in anhydrous tetrahydrofuran (40 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.3 mL). The mixture was stirred at 0° C. for 45 minutes and then a solution of (4-chloromethylphenyl)pyrrolidin-1-ylmethanone (2.0 g) in tetrahydrofuran (10 mL) was added and the resulting mixture heated at 70° C. for 24 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 by volume) to afford title compound, 1.1 g.