Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:11](=[O:12])[C:10]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:9]=2[NH:8][C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH2:1]([N:5]1[C:11](=[O:12])[C:10]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:9]=2[N:8]([CH3:24])[C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)c2c(c(C)nn2C)Nc2ncccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)c2c(c(C)nn2C)N(C)c2ncccc21

Procedure:
Prepared analogously to Example 6 from 9-(n-butyl)-1,3-dimethyl-1,4,9,10-tetrahydro-pyrazolo[4,3-e]pyrido[3,2-b][1,4]diazepin-10-one, sodium hydride, and methyl iodide in N,N-dimethylformamide with subsequent chromatographic purification.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[C:9]([O:10][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5]
Reactant: BrCCOC1CCCCO1
Reactant: O=Cc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(F)ccc(OCCOC2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To 2,6-difluoro-3-hydroxy-benzaldehyde (540, 0.150 g, 0.95 mmol) in N,N-dimethylformamide (8.0 mL) were added 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.218 g, 1.04 mmol) and potassium carbonate (0.52 g, 3.8 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 72 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (541, 180 mg, 66%).
Reaction SMILES: O.[F:2][C:3]([F:9])([F:8])[S:4]([OH:7])(=[O:6])=[O:5].[OH-].[Ca+2:11].[OH-]>C1CCCCC1>[F:2][C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5].[Ca+2:11].[F:2][C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: C1CCCCC1
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
The trace amount of trifluoromethane sulfonic acid monohydrate in the non-aqueous, cyclohexane-rich phase is neutralized with calcium hydroxide to produce calcium trifluoromethane sulfonate, which is filtered from the finished product. The calcium trifluoromethane sulfonate can be converted to trifluoromethane sulfonic acid monohydrate and the recovered trifluoromethane sulfonic acid monohydrate reused.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:10]#[N:11].ClC(Cl)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([O:23][S:29]([CH3:28])(=[O:31])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:21])[F:22])[C:10]#[N:11]
Reactant: N#CC(=C(O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)OC(=C(C#N)c1ccc(Cl)cc1Cl)c1ccccc1C(F)(F)F

Procedure:
93 mg of triethylamine was added to a mixture comprising 0.30 g of α-(2,4-dichlorophenyl)-β-hydroxy-β-(2-trifluoromethylphenyl)acrylonitrile and 7 ml of dichloroethane. Then, 96 mg of methanesulfonyl chloride was added thereto, and the mixture was reacted for 17 hours at room temperature.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:40]=[CH:39][C:15]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23](=[O:29])[CH:22]=[C:21]3[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:17])=[CH:14][CH:13]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Cl:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:30][C:21]1[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([C:15]3[CH:39]=[CH:40][C:12]([Cl:11])=[CH:13][CH:14]=3)([OH:17])[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:19]=2)[N:24]([CH3:28])[C:23](=[O:29])[CH:22]=1
Reactant: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (195 mg, 2.292 mmol, 2.00 equip) in THF (10 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.447 mL, 2.315 mmol, 2.02 equip) dropwise. After 30 minutes, a solution of 6-(4-chlorobenzoyl)-4-(3-chlorophenethyl)-1-methylquinolin-2(1H)-one (500 mg, 1.146 mmol, 1 equip, prepared as described in ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002) in HMPA (8 mL) was added dropwise and the reaction mixture was warmed to room temperature. The reaction was stirred overnight, then quenched with water and the resulting mixture extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by MPLC using methanol-dichloromethane as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one as a tan solid.
Reaction SMILES: C[C:2]([N:5](C([O-])=O)[N:6]=[C:7](C1C=CC([Cl:24])=CC=1)[C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[N:14][N:13]([CH3:16])[C:12]=2[CH:17]=1)([CH3:4])[CH3:3].[ClH:28].O.O1C[CH2:33][CH2:32][CH2:31]1>>[ClH:24].[Cl:28][C:32]1[CH:33]=[CH:3][C:2]([NH:5][NH:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[N:14][N:13]([CH3:16])[C:12]=3[CH:17]=2)=[CH:4][CH:31]=1
Reactant: C1CCOC1
Reactant: Cn1nnc2ccc(C(=NN(C(=O)[O-])C(C)(C)C)c3ccc(Cl)cc3)cc21
Agent: Cl
Solvent: O
Product: Cn1nnc2ccc(CNNc3ccc(Cl)cc3)cc21
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 10 g of intermediate 1-b in 60 ml of tetrahydrofuran under a nitrogen atmosphere were added dropwise over 15 minutes 26 ml of a borane tetrahydrofuran complex in tetrahydrofuran (1M). After stirring for 15 minutes at ±22° C. there were added 13 ml of hydrochloric acid (6N). The whole was heated to reflux and refluxed for 1.5 hours. The mixture was cooled to room temperature and 50 ml of water were added. After stirring for 1 hour, the reaction mixture was filtered. The filtrate was mixed with 75 ml of methylbenzene. The layers were separated and the aqueous layer was basified (pH 7.5-8) with NH4OH. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol by adding 3 ml of a mixture of hydrochloric acid in 2-propanol (4.8N). After stirring for 2 hours the product was filtered off, washed with 2-propanol and dried in vacuo at 50° C., yielding 2.1 g of (±)-6-[(4-chlorophenyl)hydrazinomethyl]-1-methyl-1H-benzotriazole monohydrochloride (interm. 2-e).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:20]([CH3:21])[C:6]2=[N:7][C:8]([S:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=3)=[CH:9][CH:10]=[C:5]2[N:4]=1.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[N:20]([CH3:21])[C:6]2=[N:7][C:8]([S:11][C:12]3[CH:13]=[C:14]([CH3:19])[C:15]([N+:27]([O-:29])=[O:28])=[C:16]([CH3:18])[CH:17]=3)=[CH:9][CH:10]=[C:5]2[N:4]=1
Reactant: Cc1cc(C)cc(Sc2ccc3nc(CCl)n(C)c3n2)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(Sc2ccc3nc(CCl)n(C)c3n2)cc(C)c1[N+](=O)[O-]
Reaction time: 64 h

Procedure:
To a mixture of 2-chloromethyl-5-(3,5-dimethylphenylthio)-3-methyl-3H-imidazo[4,5-b]pyridine (2.54 g), sulfuric acid (5 ml) and acetic acid (45 ml) was added nitric acid (0.52 ml) in an ice bath. The mixture was allowed to stand at room temperature for 64 hours. The reaction mixture was concentrated, diluted with water, neutralized with sodium bicarbonate and then extracted with ethyl acetate. The extract was concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=1:1 as the eluant to afford the desired compound (0.53 g, mp 133-135° C.).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@:4]([OH:12])([CH3:1])[CH2:8][CH2:7][N:6]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:11]
Reactant: COc1cc(F)ccc1C#N
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(OC)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (210 mg), 4-fluoro-2-methoxybenzonitrile (320 mg) and lithium carbonate (210 mg), the title compound was obtained as a pale-yellow solid (yield: 195.8 mg, yield: 62%).
Reaction SMILES: [CH2:1]([CH:5]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C.O>[CH2:1]([CH:5]1[CH:9]([OH:10])[C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Oc2ccc([N+](=O)[O-])cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC1Oc2ccc([N+](=O)[O-])cc2C1O
Temperature: 0 °C

Procedure:
700 mg of 2-(n-butyl)-5-nitro-3(2H)-benzofuranone were introduced into 10 ml of ethanol in a 50 ml flask and cooled to 0° C. A solution of 130 mg of NaBH4 in 5 ml of ethanol was added dropwise thereto, an intense red coloration immediately appearing. The mixture was allowed to reach room temperature and was then briefly heated to reflux. After cooling to room temperature, the reaction mixture was taken up in water and dichloromethane, the organic phase was separated off, and the aqueous phase was extracted once more with dichloromethane. Drying of the combined organic phases over sodium sulphate, removal of the solvent in vacuo and column chromatography (eluent: hexane:ethyl acetate=5:1) resulted in 400 mg (57% of theory) of 2-(n-butyl)-5-nitro-2,3-dihydrobenzofuran-3-ol.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:20]([O:22]C)=[O:21])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:20]([OH:22])=[O:21])[N:10]=3)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC)c(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a solution of methyl 3-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methoxybenzoate (4.0 g, 9.96 mmol) in methanol (50 mL)-tetrahydrofuran (100 mL) was added 5N aqueous sodium hydroxide solution (80 mL), and the mixture was stirred at room temperature for 3 hr. 6N Hydrochloric acid was added to the reaction solution to adjust the pH to about 4.0, and the reaction solution was extracted with ethyl acetate (200 mL×3). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated to give the title compound (3.70 g, 96%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]([NH:28][NH2:29])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:28][N:29]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: NNC(=O)c1ccccc1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(-c3ccccc3)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione was heated in ethanol with benzoic acid hydrazide and the resulting product heated to 250° C. to give 8-chloro-1,6-diphenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine of melting point 193.5°-194.5° C.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu][C:21]#N.C[Li]>CCOCC.O>[OH:13][CH:8]([C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: N#C[Cu]
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: COC(=O)C(O)C(C)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
1.5 g (5.9 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate dissolved in 10 ml of absolute ether were added dropwise to a cup-rate solution which had been prepared from 635 mg (7 mmol) of copper(I) cyanide dissolved in 10 ml of absolute ether and 8.14 ml (13 mmol) of a 1.6 normal methyllithium solution and had been cooled to −78° C. The solution was stirred at −78° C. for 1 h and then allowed to warm to room temperature. It was subsequently diluted with 100 ml of ether and 100 ml of water, and the ether phase was washed with dilute citric acid and with sodium bicarbonate solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel with cyclohexane/ethyl acetate mixtures to result in 250 mg (16%) of a pale yellow oil.
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]1[O:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(O)(C)C>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]1[O:30][C:27]([CH:28]=[C:6]2[CH2:5][CH2:4][CH2:3][N:2]=[C:7]2[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2Cl)o1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Agent: [Cl-]
Solvent: CC(C)O
Product: Clc1ccc(-c2ccc(C=C3CCCN=C3c3cccnc3)o2)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (103 mg, 0.41 mmol) and 5-(2,4-dichlorophenyl)furfural (128 mg, 0.53 mmol) were combined in a reaction vessel and treated with isopropanol (6 mL). The reaction vessel was sealed and the reaction was heated to 80° C. with stirring overnight. The reaction was then cooled to room temperature, concentrated under reduced pressure and treated with saturated NaHCO3(aq). This mixture was then extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The recovered material was eluted through a 20 gram column of silica gel with 10.5:7:7:0.5:0.05 (700 mL) and with 7:7:7:1:0.1 (440 mL) hexane:MtBE:CH2Cl2:MeOH:NH4OH (step gradient). One sample was recovered that slowly solidified. This solid material was re-crystallized from a mixture of hot isopropanol and hexane. The crystals were recovered by vacuum filtration, washed with 20% isopropanol in hexane and then with ether, then dried under vacuum giving 71 mg (45%) of a yellow crystalline solid. LC-MS: RT=6.17 min, [M+H]+=383.0.
Reaction SMILES: [F:1][C:2]1([F:23])[CH:6]([NH:7][C:8](=[O:15])[CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:24]>C(#N)C.C(OCC)C>[ClH:24].[F:23][C:2]1([F:1])[CH2:3][NH:4][CH2:5][CH:6]1[NH:7][C:8](=[O:15])[CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CCS(C)(=O)=O)C(F)(F)C1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CS(=O)(=O)CCC(=O)NC1CNCC1(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl 3,3-difluoro-4-{[3-(methylsulfonyl)propanoyl]amino}pyrrolidine-1-carboxylate (1.60 g, 4.5 mmol) in acetonitrile (45 mL) was added HCl (4 M in dioxane, 4.5 mL, 18 mmol, 4 mol eq). The resulting solution turned to a white suspension after 1 hr, and was stirred at ambient temperature for 3 hr. The volatiles were removed to dryness to give a white solid, which was suspended in ethyl ether (100 mL). The white solid was collected by filtration, washed with ether (20 mL) and dried to give the title product as a white solid (1.26 g, 96% yield, >95% purity, assumed 1 HCl salt). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 2 H) 8.75 (br. s., 1 H) 4.71-4.95 (m, 1 H) 3.58-3.89 (m, 3 H) 3.28-3.43 (m, 2 H) 3.16 (t, J=10.88 Hz, 2 H) 2.99 (s, 3 H) 2.67 (t, J=7.58 Hz, 2 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −108.27-−107.26 (m, 1 F) −109.70-−108.82 (m, 1 F). m/z (APCI+) for C8H14F2N2O3S 257.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:41]1[C:53]2[CH:52]([CH2:54][O:55][C:56]([N:58]3[CH2:63][CH2:62][CH2:61][CH:60]([NH:64][C:65]4[C:70]([NH2:71])=[CH:69][N:68]=[C:67]5[N:72]([S:75]([C:78]6[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=6)(=[O:77])=[O:76])[CH:73]=[CH:74][C:66]=45)[CH2:59]3)=[O:57])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH:41]1[C:53]2[CH:52]([CH2:54][O:55][C:56]([N:58]3[CH2:63][CH2:62][CH2:61][CH:60]([NH:64][C:65]4[C:70]([NH:71][C:5](=[O:7])[CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:69][N:68]=[C:67]5[N:72]([S:75]([C:78]6[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=6)(=[O:77])=[O:76])[CH:73]=[CH:74][C:66]=45)[CH2:59]3)=[O:57])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)CC1CC1
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC1CC1)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Cyclopropylacetic acid (0.300 g, 3.00 mmol), HATU (1.14 g, 3.00 mmol), and diisopropylethylamine (0.627 ml, 3.60 mmol) were added sequentially to a solution of 3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.78 g, 3.00 mmol) in DMF (50 ml) at 25° C. The reaction mixture was stirred for 1.5 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (125 ml) and EtOAc (2×150 ml). The combined organic layers were dried over Mg2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude 3-[1-benzenesulfonyl-5-(2-cyclopropyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester as a brown foam. LCMS (Method G, ESI): RT=1.24 min, m+H=676.4. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8](=O)[CH3:9])(=[O:3])[CH3:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1C=CC=CC=1>[NH:11]1[CH2:16][CH2:15][CH:14]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH:7]=[CH:8][CH3:9])[CH2:13][CH2:12]1
Reactant: CC(=O)CCCOC(C)=O
Reactant: C1CCNCC1
Solvent: O
Solvent: c1ccccc1
Product: CC=CCC(OC(C)=O)C1CCNCC1

Procedure:
A mixture of 0.5 moles of 1-acetoxypentan-4-one and 0.5 moles of piperidine in benzene is refluxed using a water separator until no more water distills from the reaction mixture. The reaction mixture is then cooled, washed and dried to afford the 4-piperidyl-1-acetoxypent-3-ene (XIX). A mixture of 5 g. of XIX in 100 ml. of dioxane is treated with an excess of methyl iodide at 20°C for 18 hours and then heated at 70°C for 6 hours. The reaction mixture is concentrated to a small volume, diluted with water and 1-acetoxy-3-methylpentan-4-one isolated by extraction with ethyl acetate. A mixture of 0.5 g. of this ketone, 100 mg. of p-toluenesulfonic acid, 3 ml. of ethyleneglycol and 100 ml. of benzene is refluxed using a water separator for 24 hours. The reaction mixture is cooled and then 100 ml. of ethanol and 2 g. of potassium hydroxide are added. This mixture is refluxed for 6 hours, cooled, diluted with water and the corresponding ethylene ketal is isolated by extraction with ethyl acetate. A solution of 0.1 moles of the ketal in 50 ml. of dimethylformamide containing 0.1 moles of triphenylphosphine is reacted with 0.1 moles of carbon tetrabromide at room temperature for 18 hours. The mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, dried and evaporated. The residue is chromatographed on 400 g. of alumina eluting with hexane-benzene and benzene to give the ethylene ketal of 1-bromo-3-methylpentan-4-one. ##EQU16##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[CH2:25]([O:24][C:22]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Brc1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(Br)cc2)CC1

Procedure:
5 g of 4-bromophenylpiperazine are placed in a 500 ml three-necked flask under a nitrogen atmosphere. 4.34 ml of triethylamine are added. The mixture is cooled in an ice bath and 3.24 ml of benzyl chloroformate are added. The mixture is allowed to return to ambient temperature. It is diluted with dichloromethane and then gentle hydrolysis is carried out. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with a saturated NaCl solution, dried over sodium sulphate, then filtered through a sintered glass filter and concentrated under vacuum. 8.43 g of 4-(4-bromophenyl)piperazine-1-carboxylic acid benzyl ester are obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[S:44][CH:45]=[CH:46][N:47]=1)CCC.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:44]1[CH:45]=[CH:46][N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:27][CH2:28][CH2:29]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nccs4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (300 mg, 0.54 mmol), 2-(tributylstannyl)thiazole (337 μA, 1.1 mmol), and PdCl2(PPh3)2 (38 mg, 0.047 mmol) in 1,2-dimethoxyethane (10 ml) was added to a crimp top microwave vial, which was then sealed and heated under microwave irradiation conditions at 130° C. for 60 min. After cooling to room temperature the mixture was poured into water and extracted into ethyl acetate. The organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography (hexane/ethyl acetate; 0-100% ethyl acetate over 60 min) to give a yellow amorphous (quant.). 1HNMR (CDCl3) 400 MHz δ: 8.18 (1H, dd, J=7.7, 1.4 Hz), 8.02 (1H, d, J=4.0 Hz), 7.75 (1H, d, J=2.9 Hz), 7.44-7.37 (3H, m), 7.32 (1H, td, J=7.5, 1.7 Hz), 7.24 (1H, d, J=2.9 Hz), 7.15 (1H, td, J=7.4, 1.2 Hz), 6.97 (1H, d, J=8.0 Hz) 6.89-6.81 (1H, m), 6.61 (1H, dd, J=7.7, 4.9 Hz), 6.48 (1H, s), 5.18 (1H, s), 2.60-2.32 (4H, m), 2.17-2.08 (1H, m), 1.93-1.84 (1H, m), 1.48-1.21 (9H, m); LC/MS [M+H]: 563.