Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([CH2:24]O)=[N:20]3)[CH:13]=[N:14][C:15]=2[O:16][CH3:17])[CH:7]=[CH:8][CH:9]=1.COCCN(S(F)(F)[F:37])CCOC>C(Cl)Cl>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[N:14][CH:13]=[C:12]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([CH2:24][F:37])=[N:20]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COc1ncc(Cn2cnc(CO)n2)cc1-c1cccc(OC(F)F)c1
Solvent: ClCCl
Product: COc1ncc(Cn2cnc(CF)n2)cc1-c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of (1-((5-(3-(difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol (Example 202, 40.0 mg, 0.11 mmol) in DCM (3 mL) was added Deoxo-Fluor® (36.64 mg, 0.17 mmol). The mixture was stirred at room temperature for 2 h. The material was adsorbed on silica and purified (FCC, SiO2, 20-100% EtOAc/hexanes) to afford the title compound (11 mg, 27%). 1H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.49-7.36 (m, 2H), 7.33 (t, J=2.2 Hz, 1H), 7.16-7.11 (m, 1H), 7.04-6.65 (m, 1H), 5.44 (s, 2H), 5.41-5.28 (m, 2H), 3.96 (s, 3H). [M+H]=365.21.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH:16]([OH:32])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:16]([C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:33])=[O:5])[S:12][CH:13]=3)[OH:32])=[CH:24][CH:23]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(O)COc2ccc(-c3ccc(F)cc3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(Sc1nc(C(O)COc2ccc(-c3ccc(F)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
2-[(4-{2-[(4′-Fluorobiphenyl-4-yl)oxy]-1-hydroxyethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (877 mg) obtained in Example 2-2 was dissolved in methylene chloride (3 mL), trifluoroacetic acid (3 mL) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated and the obtained residue was dissolved in ethyl acetate (30 mL), washed successively with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was applied to column chromatography (Moritex Corporation Purif Pack SI 60 μm size 200 was used. elution solvent: hexane/ethyl acetate=7/3→0/10). The solvent was evaporated from the obtained fraction containing the object product to give a white solid. This was dissolved in a mixed solvent of hexane and ethyl acetate with heating, and the mixture was cooled to allow precipitation of a solid to give the title compound (450.6 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH:10]=[CH:9][N:8]=1)(=O)=O.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH2:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]=[C:7]2[NH:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:12][N:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC1CCCCC1
Reactant: O=S(=O)(Oc1nccc2cnc(OCc3ccccc3)cc12)C(F)(F)F
Solvent: CN1CCCC1=O
Product: c1ccc(COc2cc3c(NC4CCCCC4)nccc3cn2)cc1
Temperature: 120 °C
Yield: 62.1 %

Procedure:
To a solution of 7-(benzyloxy)-2,6-naphthyridin-1-yl trifluoromethanesulfonate (Preparation 87, 130 mg, 0.338 mmol) in NMP (6 mL) was added cyclohexylamine (0.39 mL, 3.38 mmol). The reaction mixture was heated to 120° C. for 30 minutes. The reaction was quenched with aq. sat. NaHCO3 (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (40 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give the title compound (70 mg, 62%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCO)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCOS(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.13 mL) was added to an ice-cooled mixture of ethyl 4′-(2-hydroxyethoxy)biphenyl-4-carboxylate (0.41 g) and triethylamine (0.30 mL) in tetrahydrofuran (8 mL) with stirring. The mixture was stirred at that temperature for 30 min, at room temperature for 45 min, and at 45° C. for 1 hr. Methanesulfonyl chloride (0.13 mL) and triethylamine (0.30 mL) were added every an hour to the reaction mixture for 3 times at 45° C., and the mixture was stirred at 70° C. for 3 hrs. 1 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl 4′-(2-methanesulfonyloxyethoxy)biphenyl-4-carboxylate (0.32 g).
Reaction SMILES: [Br:1]Br.[CH:3]1([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(Cl)Cl.C(O)(=O)C>[Br:1][C:11]1([C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(c1ccccc1)C1(Br)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Temperature was kept at 20-25° C. when bromine (2.8 ml) was added slowly to a stirred mixture of cyclohexylphenyl ketone (10 g) in CH2Cl2 (50 ml) and acetic acid (1 ml). The mixture was stirred at the ambient temperature for 1 hour and extracted with 5% NaHCO3 (2×30 ml) and water (30 ml). The organic phase was dried over Na2SO4 and evaporated. Yield was 14.1 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C[Si]([C:16]#[N:17])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CCOCC.[I-].[Zn+2].[I-].O>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=1)[CH2:16][NH2:17]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C=O)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C(O)CN)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-methoxybenzaldehyde (5.0 g) in dry ether (100 ml) containing a catalytic amount of zinc iodide was added dropwise a solution of trimethylsilyl cyanide (5 ml) in dry ether. After stirring at room temperature overnight the ether solution was added to an ice-cooled suspension of lithium aluminium hydride (4.0 g) in dry ether (100 ml) under nitrogen. On completion of this addition this mixture was stirred at room temperature for 30 minutes and then boiled under reflux for 1 hour. After boiling in ice this mixture was treated with water (4 ml), 2 N sodium hydroxide solution (4 ml) and water (12 ml) and this resulting suspension was filtered and dried (MgSO4). Evaporation of the solvent gave a light green oil (3.9 g) which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]2[S:15][CH:16]=[CH:17][C:6]=12)=[O:4].[OH-].[Na+].Cl>C(O)C>[S:15]1[C:7]2=[N:8][C:9]3[C:14]([C:5]([C:3]([OH:4])=[O:2])=[C:6]2[CH:17]=[CH:16]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COC(=O)c1c2ccccc2nc2sccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c2ccccc2nc2sccc12

Procedure:
1.0 g (4.1 mmol) methyl-thieno[2,3-b]quinoline-4-carboxylate 14, 12 ml ethanol and 60 mL 1N NaOH were mixed and heated at reflux for 75 minutes. After cooling the green solution was acidified with 4N HCl to pH ˜1-2, whereupon a solid precipitated. Then the reaction mixture was extracted with 200 mL diethylether. The organic layer was separated and extracted now with 150 mL of a sodium bicarbonate solution (5%), which was acidified another time with 4N HCl to give the product 15 as a crystalline solid. The precipitate was filtered off and dried under vacuum to give 760 mg of 15.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][CH:23]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2C(=O)C3CC[C@](C)(C2=O)C3(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-methylphenyl isocyanate (0.27 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a brown solid (0.19 g, 30% yield), mp=80–82° C.; MS (−) ESI m/z=341 (M−H)−; [α]D25=−24.0° (c=1, EtOH).
Reaction SMILES: C1(N=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Te:15](Cl)(Cl)Cl)C=CC=CC=1.[BH4-].[Na+].[C:21](OC(=O)CC)(=O)[CH2:22][CH3:23].Cl>C(O)C>[CH2:22]([C:23]1[Te:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1)[CH3:21]
Reactant: CCC(=O)OC(=O)CC
Reactant: Cl[Te](Cl)(Cl)c1ccccc1N=Nc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCc1nc2ccccc2[te]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Phenylazophenyltellurium trichloride (Preparation A) (10.4 g, 0.025 mole) was suspended in ethanol (100 ml) in a flask equipped with a nitrogen gas inlet, magnetic stirrer, reflux condenser, and powder addition funnel. While stirring, under a nitrogen atmosphere, at room temperature, sodium borohydride (3.8 g, 0.10 mole) was added in increments at a rate sufficient to maintain a vigorous exothermic reaction. Stirring of the reaction mixture at room temperature was continued for 30 minutes after the addition was complete, maintaining the nitrogen atmosphere. A thermometer was inserted while still maintaining a nitrogen atmosphere and propionic anhydride (3.9 g, 0.03 mole) was added dropwise. The reaction temperature rose from 25° C. to 30° C. Upon completion of the addition, stirring was continued until the temperature returned to 25° C. Concentrated hydrochloric acid (25 ml) was added dropwise to the reaction mixture, resulting in formation of a black solid. The temperature rose to around 50° C. Stirring was continued until the temperature returned to 25° C. The black solid was removed by filtration, and washed with ethanol, and discarded. The filtrate was concentrated in a rotary evaporator, diluted with about an equal volume of water, filtered through a Celite® pad, and neutralized to a pH of about 7 with sodium bicarbonate. Extraction with diethyl ether and removal of the ether from the extracts left a red, oily semisolid, which was purified by being dissolved in dichloromethane and being applied to a thick layer silica gel chromatography plate. An ultraviolet absorbing substance separated as a pale yellow oil. This was determined to be pure by thin layer chromatography. The infrared and nuclear magnetic resonance spectra were in agreement with that expected for the structural formula.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])(C#N)[C:10]([CH3:23])([CH3:22])[CH:11]=[C:12]([O:19]CC)[N:13]2CCOCC2)[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.N.[C:38](O)(=[O:40])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:10]([CH3:23])([CH3:22])[CH2:11][C:12](=[O:19])[NH:13][C:38]2=[O:40])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: CCOC(=CC(C)(C)C(C#N)(CCCN(C)C)c1cccc(OC)c1)N1CCOCC1
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cccc(C2(CCCN(C)C)C(=O)NC(=O)CC2(C)C)c1

Procedure:
The but-1-ene product above is dissolved in acetic acid (45 ml) and sulphuric acid (30 ml) added. The resultant mixture is maintained at 100° until cyclisation is complete, as determined by working-up an aliquot and studying the infra-red spectrum of the product. The solution is cooled and poured into excess ammonia/ice, the pH adjusted to about 8 with aqueous ammonia and the solution extracted with chloroform (three times). The organic solutions are combined, dried, filtered and the solvent removed. The residual dione is crystallised and recrystallised from ethanol to give white crystals of 3-(m-methoxyphenyl)-3-(γ-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxo-piperidine, m.pt. 167°-9°.
Reaction SMILES: [O:1]=[C:2]1[CH2:9]C(C)(C)[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([OH:14])(=[O:13])[CH3:12].O=[O+][O-]>O>[O:1]=[C:2]([CH3:9])[CH2:3][C:4]([CH3:10])([CH3:5])[CH2:12][C:11]([OH:14])=[O:13]
Reactant: CC(=O)O
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: O=[O+][O-]
Solvent: O
Product: CC(=O)CC(C)(C)CC(=O)O
Reaction time: 6 h
Yield: 87 %

Procedure:
Isophorone was ozonized in the presence of 0.23% manganous acetate. For the reaction 43 grams isophorone, 120 grams acetic acid, 60 grams water and 100 milligrams Mn(OAc)2. 4H2O were charged to the reactor and ozonized in the usual manner at ambient temperature and pressure. The essentially colorless reaction mixture developed a slight greenish coloration after about three hours and after six hours was dark brown. Ozone addition was terminated at this point. The absence of active oxygen made any decomposition precautionary step unnecessary and the reaction mixture was directly treated under vacuum to strip off acetic acid and water. Vacuum distillation of the resulting crude product at 0.3 mm Hg gave an 87 percent yield of 96.5% pure 5-keto-3,3-dimethylhexanoic acid boiling in the range 95° C. to 100° C.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Br:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[Br:9][CH2:10][C:11]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][C:1]=1[CH3:8])=[O:12]
Reactant: O=C(Cl)CBr
Reactant: Cc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C)c(C(=O)CBr)c1
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
A mixture of 10.60 g (0.10 mol) of para-xylene and 16.53 g (0.105 mol) of α-bromoacetyl chloride in 300 mL of 1,2-dichloroethane was cooled in an ice bath under an atmosphere of dry N2 and treated portionwise with 14.15 g (0.106 mol) of aluminum chloride. The reaction mixture was stirred for 30 minutes at 0°-5° C. and then for 2.5 hours at room temperature. The mixture was then poured onto ice and the aqueous layer was acidified with concentrated HCl. The organic layer was separated and the aqueous layer was extracted twice with methylene dichloride. The combined organic extracts were dried with brine solution and with magnesium sulfate. The solvent was evaporated to give 23.87 g of an amber oil which was for use in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>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>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=2)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: C#Cc1cncn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1cncn1C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.4 g (5.3 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (A-3) and 900 mg (8.5 mmol) 5-ethynyl-1-methyl-1H-imidazole using 10 mg (0.05 mmol) CuI, 112 mg (0.03 mmol) PdCl2(PPh3)2, 5.3 mL (5.3 mmol) of 9-methoxy-9-BBN and 1.3 mL (9.5 mmol) triethylamine in 125 mL degassed and dry acetonitril. The product precipitates from the reaction mixture and is filtered off. Yield: 780 mg (54%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][NH2:13].N1([O:25][S:26]([CH:29]([CH3:31])[CH3:30])(=O)=[O:27])C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[F:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][NH:13][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:27])=[O:25]
Reactant: CC(C)S(=O)(=O)On1nnc2ccccc21
Reactant: COc1ccc(C(C)(O)CN)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(O)CNS(=O)(=O)C(C)C)c(F)c1
Temperature: 120 °C

Procedure:
2-(2-Fluoro-4-methoxy-phenyl)-2-hydroxy-propylamine hydrochloride was converted to the free base by partitioning between ethyl acetate and 1 M NaOH. The amine (1.0 g, 5.02 mmol) was combined with propane-2-sulfonic acid benzotriazol-1-yl ester (1.3 g, 5.52 mmol) in DMF (25 mL) and heated at 120° C. for 2 hr. then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and extracted with 1 M HCl. The organic layer was separated and washed with water and saturated NaCl, dried (MgSO4), filtered, and concentrated to a yellow oil which was used in the next step without purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.C([N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:40]4[CH:41]=[N:37][NH:38][CH:39]=4)=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1C(Cc2c(Cl)cc(-c3cn[nH]c3)cc2Cl)CCN1C1CCCCC1

Procedure:
Using the method of Example 81 and using 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.238 g, 2.61 mmol), 1-boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.3 g, 7.83 mmol) tetrakis(triphenylphosphine)palladium (0.302 g, 0.261 mmol), dimethoxyethane (15 mL) and sodium carbonate (2M, 4.6 mL) gives the title compound. Purify the crude material over silica gel (1/1 hexane in ethyl acetate to 1/3 hexane in ethyl acetate) to yield 0.545 g (53%) of the title compound: mass spectrum (m/z): 394(M+2).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]4[N:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]3[C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([C:36]3([NH:40]C(=O)OC(C)(C)C)[CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].[ClH:48].O1CCOCC1>C(Cl)Cl>[ClH:48].[ClH:48].[ClH:48].[NH2:40][C:36]1([C:33]2[CH:32]=[CH:31][C:30]([C:29]3[N:15]4[C:16]5[CH:28]=[CH:27][CH:26]=[N:25][C:17]=5[NH:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:14]4=[N:13][C:12]=3[C:8]3[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:10][CH:9]=3)=[CH:35][CH:34]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4cccc(NS(C)(=O)=O)c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 89.7 %

Procedure:
tert-Butyl {1-[4-(2-{3-[(methylsulfonyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (13.7 mg, 0.0211 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 11.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (12.5 mg, 89.7%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 9.76 (s, 1H), 8.67 (br s, 2H), 8.62 (s, 1H), 8.10 (dd, J=4.6, 1.4 Hz, 1H), 7.94 (dd, J=7.6, 1.6 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.49-7.47 (m, 1H), 7.41-7.29 (m, 4H), 7.25 (t, J=7.8 Hz, 1H), 7.19-7.08 (m, 3H), 6.88 (dd, J=7.8, 1.4 Hz, 1H), 6.73 (dd, J=8.0, 4.6 Hz, 1H), 2.90 (s, 3H), 2.61-2.48 (m, 4H), 2.25-2.12 (m, 1H), 1.89-1.76 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:15])[O:12][C:13](=[O:14])[C:3]1=2.[CH3:16][OH:17]>>[CH3:16][O:17][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[C:13]([OH:12])=[O:14])=[O:15]
Reactant: Cn1c2c(c3ccccc31)C(=O)OC2=O
Reactant: CO
Product: COC(=O)c1c(C(=O)O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
An ice cold solution of dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol) in N,N-dimethylformamide (DMF) (31.5 ml) was treated with NaH (0.617 g, 15.44 mmol) and methyl iodide (0.881 ml, 14.15 mmol) and warmed to 75° C. After 8 h, the reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl. The combined organics were washed with water (3×), brine, dried (MgSO4), filtered and concentrated. The residue was treated with a solution of KOH (8.66 g, 154 mmol) in EtOH (200 mL) and heated to reflux (95° C. bath temp). After 8 h, the reaction mixture was cooled to ambient temperature, diluted with EtOAc and the layers partitioned. The aqueous layer was extracted with EtOAc (2×) and acidified with 1 M HCl to pH 3. The aqueous layer was then extracted with EtOAc and the organics were washed with brine, dried (MgSO4), filtered and concentrated to afford 1-methyl-1H-indole-2,3-dicarboxylic acid (2.82 g, 12.87 mmol, 100% yield) as a white solid. The acid was suspended in DCM (30 mL) and treated dropwise with TFAA (4.39 ml, 32.2 mmol). After 2 h, the reaction mixture was concentrated in vacuo to afford 4-methyl-1H-furo[3,4-b]indole-1,3(4H)-dione as a purple solid. The anhydride was suspended in MeOH (100 mL) and stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo to afford 3-(methoxycarbonyl)-1-methyl-1H-indole-2-carboxylic acid (2.95 g, 12.65 mmol, 98% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ=8.00 (s, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 7.40-7.33 (m, 1 H), 7.28 (s, 1 H), 3.82 (d, J=5.7 Hz, 6 H); LCMS (m/z) ES+=234 (M+1).