Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCOCC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)CCO[Si](C)(C)C(C)(C)C
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(CCO[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 1 h

Procedure:
The product of Example 457A (2.0 g, 9.88 mmol) in anhydrous THF (50ml) under at 0 C under nitrogen was reacted with phenylmagnesium bromide as a 3.0M solution in ether (5.0 ml, 15 mmol) dropwise via syringe then stirred for one hour. The reaction was quenched by the drop wise addition of a saturated solution of ammonium chloride and the reaction was partitioned with ether and water. The combined organics were dried over magnesium sulfate and concentrated in vacuo to give the desired compound as a clear oil (2.71 g, quantitative).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[C:20](C=CCC)[CH:19]=2)(=[O:17])=[O:16])C=CC=1C(C)(C)C)=CCC.[CH3:32][SnH:33]([CH3:35])[CH3:34]>[Hg]>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([S:15]([CH2:7][CH2:6][CH2:5][CH2:1][Sn:33]([CH3:35])([CH3:34])[CH3:32])(=[O:17])=[O:16])=[CH:19][CH:20]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCC=Cc1cc(S(=O)(=O)c2ccc(C(C)(C)C)c(C=CCC)c2)ccc1C(C)(C)C
Reactant: C[SnH](C)C
Agent: [Hg]
Product: CC(C)(C)c1ccc(S(=O)(=O)CCCC[Sn](C)(C)C)cc1
Yield: 20.3 %

Procedure:
An 80 ml, two-necked, pyrex glass Schlenk reaction tube containing a Teflon coated magnetic stir bar was swept thoroughly with nitrogen and maintained in an air-free condition. The tube was charged with 10.7 g (42.5 mmoles) of 3-butenyl-4-t-butylphenyl sulfone and 7.0 g (42.5 mmoles) of trimethyltin hydride, stoppered, and placed in a 20° C. water bath. The tube was irradiated for 70 hours by a 100 watt mercury vapor lamp which was situated in a large test tube and placed in the same bath 5-10 cm. from the reaction tube. Recrystallization of the solid product from petroleum ether afforded 3.6 g of 4-(4-t-butylphenylsulfonyl)butyltrimethylstannane, m.p. 80°-81.8° C. The presence of both the sulfonyl and trimethyltin moieties was indicated by strong infrared absorption bands at 1300 cm-1, 1282 cm-1, 1147 cm-1 (--SO2 --) and 780 cm-1 [(CH3)3Sn--] employing a KBR disc. Nuclear magnetic resonance spectroscopy (NMR) showed the following:
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:20][CH2:21][C:22]([NH:1][C@H:2]([C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:3][OH:4])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: N[C@@H](CO)c1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N[C@@H](CO)c1cc(F)cc(F)c1
Reaction time: 0.33 h

Procedure:
To a solution of (2R)-2-amino-2-(3,5-difluorophenyl)ethanol from Step B (630 mg, 3.64 mmol) and triethylamine (0.51 mL, 3.64 mmol) in CH2Cl2 (40 mL) at 0° C. was added chloroacetyl chloride (0.29 mL, 3.64 mmol). After 20 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=250 (M+1).
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[C:8](/[CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)\[CH3:9])=[O:6])([CH3:4])[CH3:3].CO.[BH4-].[Na+]>O1CCCC1>[CH3:1][C:2]([S@:5]([NH:7][CH:8]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:9])=[O:6])([CH3:3])[CH3:4]
Reactant: C/C(=N\[S@](=O)C(C)(C)C)C1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(N[S@](=O)C(C)(C)C)C1CCOCC1
Temperature: -32.5 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of (R,E)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethylidene)propane-2-sulfinamide (1.25 g, 5.4 mmol) in tetrahydrofuran (6 mL) was added methanol (692 mg, 21.6 mmol) and NaBH4 (821 mg, 21.6 mmol) at −65° C. under N2. The reaction was stirred at −65-0° C. for 2 h. Then the reaction was quenched by water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 and concentrated in vacuo to give crude (R)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)Propane-2-sulfinamide (1.2 g, 52.1%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccc(C#N)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A mixture of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.267 g, 1.00 mmol), 4-bromomethyl-2-fluoro-benzonitrile (0.321 g, 0.1.50 mmol), DIPEA (0.259 g, 2.00 mmol) and KI (0.017 g, 0.10 mmol) in dry CH3CN (10 mL) was stirred at 60° C. for 16 h. After that period of time the CH3CN was removed by evaporation under vacuum, and saturated aqueous NaHCO3 (20 mL) was added. The aqueous mixture was extracted with CH2Cl2 (3×30 mL, and the extract was dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on a silica gel column (1000:30:1, CH2Cl2/CH3OH/NH4OH), affording 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-fluoro-benzonitrile as a white foam (0.400 g, 100%). 1H NMR (CDCl3) δ 1.65-1.80 (m, 3H), 2.09-2.14 (m, 1H), 2.20-2.38 (m, 2H), 2.44 (s, 6H), 3.58 (s, 2H), 4.16 (s, 1H), 4.20 (s, 1H), 6.37-6.43 (m, 2H), 6.93-7.03 (m, 3H), 7.23 (d, 2H, J=7.5 Hz), 8.35 (dd, 2H, J=0.9, 4.5 Hz).
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][CH:11]([C:23](=[O:25])[CH3:24])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:24][C:23]1[O:25][C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[N:10][C:11]=1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: CC(=O)C(CC(=O)OCc1ccccc1)NC(=O)C1(C)CCCCC1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1oc(C2(C)CCCCC2)nc1CC(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
A mixture of benzyl 3-(1-methylcyclohexylcarbonylamino)-4-oxovalerate (1.2 g), toluene (20 ml) and phosphorus oxychloride (2.0 ml) was refluxed with stirring for 4 hours. The solvent was distilled off and aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl ether and the ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was purified by chromatography on silica gel (13 g) [eluent: hexaneacetone (9:1)] to give benzyl 5-methyl-2-(1-methylcyclohexyl)- 4-oxazoleacetate; yield 1.0 g (87.7%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)(=[O:3])[CH3:2]>ClCCl.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)indole (step 1). m.p.: 152-154° C. (dichloromethane/hexane)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=[C:16]([C:17]3[S:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C(N)C1C=CC=CC=1.CC1SC(C=C[N+]([O-])=O)=CC=1>C1(C)C=CC=CC=1>[CH2:23]([N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16]([C:17]2[S:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[CH:15]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2cn(Cc3ccccc3)c3c2CN(C(=O)OC(C)(C)C)CC3)s1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(C=C[N+](=O)[O-])s1
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Product: Cc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Benzyl-3-(5-methyl-thiophen-2-yl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. A mixture of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.54 g) and 300 μL of benzylamine in toluene (10 mL) was heated at reflux for 6 h using a Dean-Stark apparatus. The solution was cooled to RT and 0.47 g of 2-methyl-5-(2-nitro-vinyl)-thiophene was added. The mixture was stirred for 16 h at RT and then was concentrated in vacuo. The residue was chromatographed on SiO2 (1 to 30% EtOAc/hexanes) to afford 281.9 mg of the desired compound. TLC (SiO2, 33% EtOAc/hexanes): Rf=0.54.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.CN.ClCCl.[CH2:20]([N:22](CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH3:20])=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 60 h

Procedure:
A mixture of 2-chloro-5-nitro-benzoyl chloride (502 mg, 2.3 mmol), methylamine hydrochloride (213 mg, 3.1 mmol), dichloromethane (10 ml), and triethylamine (0.84 ml, 6.0 mmol) was stirred for 60 hours. The mixture was treated with ethyl acetate (25 ml). The solution was washed with a mixture of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1:1, 2×20 ml), washed with aqueous sodium carbonate solution (1 M, 20 ml), dried over sodium sulfate, and concentrated under reduced pressure to provide 2-chloro-N-methyl-5-nitro-benzamide.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][CH3:20])[CH:18]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[C:40]([O:39][C:38]([NH:37][C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][CH3:20])[CH:18]=2)[N:3]=1)=[O:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CCn1cc(-c2nc(Cl)cc(C#N)c2C(=O)OC)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc(C#N)c2C(=O)OC)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a solution of methyl 6-chloro-4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)nicotinate (201 mg, 0.691 mmol) in DMF (1 mL) was added DIPEA (0.242 mL, 1.383 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (237 mg, 1.106 mmol). The reaction mixture was stirred at 100° C. overnight, after which the solvent was removed, and the resulting crude material was diluted in MeOH (5.0 mL) and purified via reverse phase preparative HPLC. The collected fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (62 mg, 19%). [M+H] calc'd for C24H32N6O4, 469. found, 469.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[C:20]([C:24]1[O:28][N:27]=[C:26]([NH2:29])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[O:28][N:27]=[C:26]([NH:29][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)Nc3cc(C(C)(C)C)on3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (5-tert-butyl-isoxazol-3-yl)-amine to afford the title compound. MS: m/e=381 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-])=O>[Cu]>[C:2]1([N:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:20]3[CH:19]=[CH:18][C:17]([N:14]([C:2]4[CH:7]=[CH:6][C:5]([C:2]5([C:20]6[CH:19]=[CH:18][C:17]([N:14]([C:2]7[CH:7]=[CH:6][C:5]([C:20]8[CH:19]=[CH:18][C:17]([N:14]([C:2]9[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=9)[C:2]9[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=9)=[CH:22][CH:21]=8)=[CH:4][CH:3]=7)[C:2]7[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=7)=[CH:22][CH:21]=6)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]5)=[CH:4][CH:3]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:22][CH:21]=3)=[CH:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(C5(c6ccc(N(c7ccccc7)c7ccc(-c8ccc(N(c9ccccc9)c9ccccc9)cc8)cc7)cc6)CCCCC5)cc4)cc3)cc2)cc1
Yield: 48.9 %

Procedure:
9.05 g (0.01 mol) of 1,1-bis[p-[N-(4'-anilino-4-biphenylyl)anilino]phenyl]cyclohexane thus obtained, 4.49 g (0.022 mol) of iodobenzene, 2.90 g (0.021 mol) of anhydrous potassium carbonate, 0.32 g (0.005 mol) of copper powder, and 15 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 198° C. to 213° C. for 19 hours. The reaction product was then extracted with 150 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated. To the concentrate was then added 110 ml of n-hexane to recover a crude crystal. The crude crystal thus recovered was then purified by column chromatography (carrier: silica gel; elute: 2/3 mixture of toluene and n-hexane) to obtain 5.17 g (yield: 48.9%) of 1,1-bis[p-[N-(4'-diphenylamino-4-biphenylyl)anilino]phenyl]cyclohexane. The melting point of the product was indefinite.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)(=[O:35])=[O:34])[C:27]=2[F:41])[CH:5]=[CH:4][N:3]=1.[CH3:42][Zn]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:41][C:27]1[C:28]([NH:32][S:33]([C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][C:26]=1[C:9]1[N:10]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[S:12][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:42])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
1,1-dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)-amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate (150 mg, 0.242 mmol) was dissolved into 1,4-dioxane (3 mL) and the solution was degassed for 10 min. PdCl2(dppf)-CH2Cl2 adduct (13.83 mg, 0.017 mmol) and dimethylzinc (0.242 mL, 0.484 mmol) were added to the reaction mixture. The reaction mixture was stirred at 80° C. for 1 h. The reaction was quenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (40% to 100% EtOAc/hexane) to give the title compound (118 mg). MS (ESI): 600.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:25])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH3:24][C:22]1[NH:21][N:20]=[C:19]([NH:18][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:25])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=3)[N:17]=2)[CH:23]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(Nc2nn(-c3ccc(N)cc3)c(=O)c3ccccc23)n[nH]1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-n2nc(Nc3cc(C)[nH]n3)c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Amino-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-phthalazin-1-one (C-2, 0.050 g, 0.15 mmol) was dissolved in pyridine (1 ml) at 0° C. Acetylchloride (0.024 ml, 0.33 mmol) was added and stirring was continued for 30 min at 0° C. before the mixture was allowed to warm to room temperature. The solvent was evaporated after 2 h stirring at room temperature. The residue was diluted in MeOH (1 ml) and treated with conc. NH3 (1 ml). The title compound was obtained after stirring at room temperature for 24 h and evaporation of the solvents in vacuum (0.016 g, 29%). 1H-NMR: (400 MHz, D6-DMSO) 11.93 (1H, s), 10.08 (1H, s), 9.26 (1H, s), 8.49 (1H, d), 8.36 (1H, d), 7.88–7.98 (2H, m), 7.61–7.69 (4H, m), 6.24 (1H, s), 2.19 (3H, s), 2.08 (3H, s); MS (API+)=375 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>CN(C)C=O>[N:1]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3[C:15](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]2=[O:23])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1cncn1
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
A mixture of 9.0 g of 1H-1,2,4-triazole, 6.24 g of approximately 50% sodium hydride in oil and 130 ml of dimethylformamide was stirred for 1.5 hours. Then, 33 g of N-(4-bromobutyl)phthalimide was added and this mixture was heated on a steam bath for 6 hours, then concentrated to a solid residue. Water and methylene chloride were added, the organic layer was separated, washed with water, dried and concentrated to a residue. This residue was recrystallized from ethanol, giving 27.3 g of 2-[4-(1H-1,2,4-triazol-1-yl)butyl]-1H-isoindol-1,3(2H)-dione.
Reaction SMILES: [F:1]/[C:2](=[CH:6]\[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)/[C:3]([OH:5])=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1]/[C:2](=[CH:6]\[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)/[C:3]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[CH:28][CH:27]=1)=[O:5]
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C(O)/C(F)=C/c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)/C(F)=C/c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
The mixture of (Z)-2-fluoro-3-(pyridin-3-yl)acrylic acid (100 mg, 0.598 mmol),4-(phenylsulfonyl)aniline (140 mg, 0.598 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (341 mg, 0.897 mmol), DIEA (232 mg, 1.795 mmol) in DMF (Volume: 10 ml) was stirred at RT for overnight, removed DMF, extracted with EtOAc, washed with 1N NaOH, brine, dried and the biotage purification afforded the product (51 mg, 23%).
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13].CC(C)([O-])C.[K+].C1COCC1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c2cccc3c2n1CC=C3
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1n(Cc2ccccc2)c2cccc3c2n1CC=C3
Reaction time: 0.17 h

Procedure:
A mixture of 4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (I, J. Heterocyclic Chem., 19, 837-49 (1982), 1.0 g, 5.8 mmol) in DMF (10 (1) is cooled to 0° and treated with potassium t-butoxide in THF (1.98 M, 3.2 ml, 6.3 mmol) maintaining the reaction temperature at 0°. The resulting mixture is stirred at 0° for 10 minutes. Benzyl bromide (0.73 ml, 6.1 mmol) is then added while maintaining the reaction temperature at 0°. After 1 hr, the mixture is partitioned with methyl t-butyl ether (MTBE) from water followed by several water washes. The MTBE phase is concentrated under reduced pressure. The concentrate is cooled to 0°, filtered and washed two times with 0° MTBE. The product is dried at 50° under reduced pressure with a nitrogen purge to give the title compound, CMR (CDCl3, 100 MHz) L 153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36, 44.95 and 42.37.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14].[CH3:17][N:18]1CCCC1=O>>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14])#[N:18]
Reactant: CN1CCCC1=O
Reactant: COC(=O)C1CCOc2cc(F)c(Br)cc21
Product: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Temperature: 160 °C
Yield: 77 %

Procedure:
Methyl 6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (415 mg, 1.44 mmol) was diluted with N-methylpyrrolidone (5 mL) followed by the addition of Cu(I)CN (643 mg, 7.18 mmol). The reaction was bubbled with argon for 20 minutes, then heated at 160° C. under a slight argon bubble for 6 hours. The reaction was cooled to ambient temperature and loaded directly onto a Biotage 25 column eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (260 mg, 77.0% yield).