Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.C([O:7][C:8]([C:10]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:17])[CH3:16])[C:11]=1[CH:18]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:18]2[C:11]3[N:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:14][C:10]=3[C:8](=[O:7])[N:19]2[C@H:20]2[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(N[C@H]1CC[C@H](O)CC1)c1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)n1ccc2c1C(c1ccc(Cl)cc1)N([C@H]1CC[C@H](O)CC1)C2=O
Temperature: 75 °C
Reaction time: 25 h

Procedure:
A solution of trimethylaluminium (2M in toluene) [75-24-1] (16.75 mmol) was added to a solution of 2-[(4-chloro-phenyl)-(trans-4-hydroxy-cyclohexylamino)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step F2) (5.58 mmol) in toluene (25 mL) and the mixture was stirred at 75° C. for 25 h. The mixture was cooled to rt, poured onto a stirring ice-cold solution of saturated Rochelle's salt and then diluted with EtOAc. The phases were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a beige solid. tR: 3.99 min (HPLC 1); ESI-MS: tR=0.97 min, [M+H]+ 373/375 (LC-MS 1); TLC: Rf=0.27 (EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[O:18].[CH3:19][Mg]Br.[NH4+].[Cl-].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH3:19])[OH:18]
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 0 °C
Yield: 93.5 %

Procedure:
A suspension of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (35 g, 107 mmol) in dry THF (210 mL) under nitrogen atmosphere was cooled to 0° C. and a solution of methylmagnesium bromide (3.0M solution in diethyl ether; 107 mL, 320 mmol) in dry THF (70 mL) was added over 10 minutes via an addition funnel. After complete addition a saturated aqueous solution of NH4Cl (125 mL) was added slowly to the stirring reaction mixture, keeping the internal temperature below 30° C. Water was added and the mixture was extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate before concentrating under reduced pressure to afford 7-bromo-3-chloro-1-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol (34.33 g, 100 mmol).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:11]1([CH2:18][CH:19]=[CH2:20])[CH2:15][NH:14][C@@H:13]([CH2:16][OH:17])[CH2:12]1)[CH:9]=[CH2:10].[S:21](Cl)(Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH2:18]([C:11]1([CH2:8][CH:9]=[CH2:10])[CH2:15][N:14]2[S:21](=[O:23])(=[O:22])[O:17][CH2:16][C@H:13]2[CH2:12]1)[CH:19]=[CH2:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: C=CCC1(CC=C)CN[C@@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(CC=C)C[C@@H]2COS(=O)(=O)N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
A solution of triethylamine (2.460 ml, 17.65 mmol) and (R)-(4,4-diallylpyrrolidin-2-yl)methanol (1.60 g, 8.83 mmol) in DCM (44.1 ml) was cooled to −78° C. To this mixture was added sulfuryl chloride (0.859 ml, 10.59 mmol) in DCM (44 mL) dropwise in 1 h. The reaction was maintained at this temperature for 3 h, then allowed to warm to room temperature and stirred overnight. The mixture washed with aq. 1 N HCl (30 ml×2), brine (30 ml), dried, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide (R)-5,5-diallyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (0.66 g, 2.71 mmol, 30.7% yield) as light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.71-5.86 (m, 2H), 5.10-5.20 (m, 4H), 4.57 (dd, J=6.63, 8.76 Hz, 1H), 4.24-4.36 (m, 1H), 4.19 (dd, J=4.66, 8.76 Hz, 1H), 3.21-3.32 (m, 2H), 2.19-2.29 (m, 4H), 2.03-2.18 (m, 1H), 1.57-1.63 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(Cl)(Cl)Cl>[CH3:3][CH:4]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: CC(C)CCCC(C)CCOCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)CCCC(C)CCOCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.2 %

Procedure:
Sodium hydride (1.79 g 60% dispersion in oil, 1.07 g, 44.8 mmol) was weighed out in a 250 mL round bottom flask. The mineral oils were washed out with hexane (3×15 mL). DMF (30 mL) was added, followed by (3,7-dimethyloctanyl)oxybutyl bromide (3 g, 10.2 mmol) and then the reaction mixture was stirred at room temperature under N2 for a couple of minutes. Imidazole (3.50 g, 51.4 mmol) was added in portions while cooling the reaction mixture in an ice bath. The addition of the imidazole was exothermic causing the mixture to become a milky off-white and then clear yellow in colour after complete addition of the imidazole. Stirring was continured under N2 at room temperature for 3 d. The reaction mixture was diluted with chloroform (100 mL) to form a thick cloudy mixture and washed with water (2×50 mL). The organic layer was dried (Na2SO4) and the solvent was removed at reduced pressure and then under high vacuum to give the product as a brown clear oil (3.38 g).
Reaction SMILES: [CH:1]1[C:6](C=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].[OH-].[K+]>C(Cl)Cl.CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([OH:17])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
commercial piperonal (Aldrich) (60 g) was dissolved in CH2Cl2 (500 ml), m--chloroperoxybenzoic acid (MCPBA) (90 g) added in portions and left to stir at room temperature (18 hrs.). The precipitate was filtered off and washed with CH2Cl2. The combined filtrate was then washed with cold saturated Na2CO3 solution, followed by H2O, dried over anhy. MgSO4 and evaporated to dryness. The resulting formate ester, δ (CDCl3, 300 Hz): 5.99 (2H, s, OCH2O), 6.56 (1H, d, J=8 Hz, H-6), 6.65 (1H, d, J=2 Hz, H-2), 6.70 (1H, d, J=8 Hz, H-5), 8.25 (1H, s, formate), was dissolved in MeOH (250 ml) and mixed with a solution of 30 g KOH in 200 ml MeOH. The reaction mixture was left at room temp for 15 hrs., evaporated to dryness, the residue dissolved in water (300 ml), acidified to neutral by dilute HCl (6N) and extracted with ethyl acetate. The organic layer was washed with NaHCO3 followed by water, dried over anhy. MgSO4 and evaporated to dryness. The crude product (57 g) was recrystallized from hexane (48 g), to yield colourless crystals, mp. 54°-55° C.; IR νmaxKBr cm-1 : 3580, 1625; UV νmaxMeOH nm (ε): 300.1 (2436), 234.2 (2269), 215.3 (2697), with KOH in methanol 314.2 (2477), 242.6 (2781), 225.6 (2746); 1H-NMR δ (CDCl3): 5.90 2H, s, OCH2O), 6.15 (1H, dd, J=2.4, 8.0 Hz, H-6), 6.24 (1H, d, J=2.4 Hz, H-2), 6.34 (1H, d, J=8.0, Hz, H-5), 4.68 (1H, bs, exchanged with D2O, phenolic); HRMS m/z: 138.0316 (M+, 100, C7H6O3), 137.0238 (M+ -H, 88.42, C7H5O3).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.Cl.[CH3:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C>C(#N)C.CN(C)C=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:28]2[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][CH3:24])[CH2:27]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: CNC1CCCNC1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC1CCCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Yield: 29.5 %

Procedure:
A suspension of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.039 g), 3-methylaminopiperidine hydrochloride (1.5 g) and triethylamine (2.5 g) in acetonitrile (30 ml) and N,N-dimethylformamide (10 ml) was refluxed overnight. Concentration of thereaction mixture followed by purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=15:5:1) gave a yellow crystalline substance [MS m/e: 404 (M+)]. The crystalline substance thus obtained was recrystallized from ethanol to afford 5-amino-7-(3-methylaminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg) as yellow needles. m.p. 265°-275° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]CC2C=CC(OC)=CC=2)[C:5]([C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:6]1[C:5]([C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COC(=O)c1ccc(Cl)nc1NCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)c1ccc(Cl)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of methyl 6-chloro-2-[(4-methoxybenzyl)amino]pyridine-3-carboxylate (1.0 g) in trifluoroacetic acid (5 ml) was added anisole (0.5 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene. The obtained oil residue was diluted with ethyl acetate (80 ml), and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (596 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14]#[N:15])[CH:9]=[CH:10][CH:11]=1.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][CH2:13][C:14]1[NH:23][N:22]=[N:21][N:15]=1
Reactant: Cc1cccc(C)c1COc1cccc(CCC#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1COc1cccc(CCc2nnn[nH]2)c1
Temperature: 90 °C

Procedure:
A mixture of 3-(3-(2,6-dimethylbenzyloxy)phenyl)propanenitrile (Step C, 2.62 g, 9.9 mmol), sodium azide (0.899 g, 13.8 mmol) and ammonium chloride (0.740 g, 13.8 mmol) in dry DMF (20 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, diluted with water and extracted with EtOAc (30 ml×4). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:592.5:7.5) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[NH:28][CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1>N1C=CC=CC=1>[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=4[Cl:1])=[CH:8][CH:9]=3)=[O:12])[CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2cc(Cl)ccc2Cl)cc1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1)c1cc(Cl)ccc1Cl

Procedure:
As described for Example 1, 5 mmol of 4-[(2,5-dichlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[O:14])=[N:11][CH:12]=1.[OH-:18].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:18])=[O:14])=[N:11][CH:12]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(NCc2cccc(Cl)c2)cn1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(NCc2cccc(Cl)c2)cn1

Procedure:
4.93 g of 5-(m-chlorobenzylamino)-pyridine-2-carboxaldehyde are added in small portions to the cold stirring solution consisting of 70.4 g of silver nitrate in 150 ml of water and 33.1 g of sodium hydroxide in 150 ml of water. The mixture is stirred 10 minutes after the last of the aldehyde is added and filtered. The yellow filtrate is cooled and 12 N hydrochloric acid is added until the pH is 5. A solid precipitates which is collected by filtration and crystallized from methanol, to yield the 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid melting at 170°-174°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:31].Cl.[NH2:36][CH2:37][CH2:38][NH:39][S:40]([CH3:43])(=[O:42])=[O:41].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CO.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH2:27][NH:36][CH2:37][CH2:38][NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:31]
Reactant: CS(=O)(=O)NCCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
At room temperature, 10.0 g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde, 6.5 g of compound N-(2-aminoethyl)methanesulfonamide hydrochloride, and 14.6 g of triethylamine in the mixture of dichloromethane/methanol (3:1) were stirred overnight, then cooled with ice-bath to 0° C., and 1.4 g of sodium borohydride was added at that temperature. The mixture was warmed to room temperature, stirred overnight, saturated sodium bicarbonate was added to quench the reaction, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 5.7 g of the desired product, yield 45.0%.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:40]=[C:39]([N:41]4[CH2:46][CH2:45][N:44]([CH2:47][C:48]5[CH2:53][CH2:52][C:51]([CH3:55])([CH3:54])[CH2:50][C:49]=5[C:56]5[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=5)[CH2:43][CH2:42]4)[CH:38]=[CH:37][C:13]=3[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[C:22]([N+:34]([O-:36])=[O:35])[CH:21]=3)(=[O:19])=[O:18])=[O:15])[CH:9]=2)[NH:4][CH:3]=1.C([OH:65])C>Cl>[Cl:62][C:59]1[CH:58]=[CH:57][C:56]([C:49]2[CH2:50][C:51]([CH3:55])([CH3:54])[CH2:52][CH2:53][C:48]=2[CH2:47][N:44]2[CH2:45][CH2:46][N:41]([C:39]3[CH:38]=[CH:37][C:13]([C:14]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[C:22]([N+:34]([O-:36])=[O:35])[CH:21]=4)(=[O:18])=[O:19])=[O:15])=[C:12]([O:11][C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[NH:4][C:3](=[O:65])[CH2:2]5)[CH:40]=3)[CH2:42][CH2:43]2)=[CH:61][CH:60]=1
Reactant: CCO
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]cc(Cl)c5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: Cl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5c(c4)CC(=O)N5)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
A solution of EXAMPLE 265E (38 mg) in ethanol (5 mL) and 1 N aqueous HCl (5 mL) was stirred at 85° C. for 7 hours. The mixture was cooled to ambient temperature and concentrated. The residue was purified on reverse-phase HPLC on a C18 column using a water-acetonitrile gradient with ammonium acetate buffer to give the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.30 (br s, 1H), 10.33 (s, 1H), 8.61 (t, 1H), 8.54 (d, 1H), 7.84 (dd, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.18 (d, 1H), 7.06 (d, 2H), 6.84 (s, 1H), 6.80 (d, 1H), 6.74 (d, 1H), 6.67 (dd, 1H), 6.20 (d, 1H), 3.85 (dd, 2H), 3.43 (s, 2H), 3.27 (t, 2H), 3.10 (br. s, 4H), 2.77 (br. s, 2H), 2.25-2.10 (m, 6H), 1.97 (br. s, 2H), 1.90 (m, 1H), 1.62 (dd, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Br[C:26]1[C:27]2[CH:36]=[CH:35][O:34][C:28]=2[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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]>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:8][C:7]=2[C:26]2[C:27]3[CH:36]=[CH:35][O:34][C:28]=3[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=2)[CH2:2][CH2:3]1
Reactant: Cn1cc(Br)c2ccoc2c1=O
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c2ccoc2c1=O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
A mixture of 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (115 mg, 0.33 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (75 mg, 0.33 mmol), K3PO4 (175 mg, 0.83 mmol), Pd(dppf)Cl2 (24 mg, 10%) in dioxane/H2O (2.2 mL/200 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 70° C. for 90 min. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue. The resulting residue was purified by prep-HPLC to afford the title compound (60 mg, 49%) as a white solid. LCMS (M+H)+=374.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:6]#[CH:7])[CH2:3][CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:8])([C:3]#[CH:4])[CH2:6][CH2:7][N:32]1[C:28](=[O:38])[C:29]2[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31]1=[O:33]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#CC(C)(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC(C)(C)CCN1C(=O)c2ccccc2C1=O
Yield: 52.4 %

Procedure:
To a solution of 3,3-dimethyl-4-pentyn-1-ol (6.3 g) synthesized according to the method described in Chemistry A European Journal, 2005, 11, pp. 308-320, triphenylphosphine (29.4 g), and phthalimide (16.5 g) in tetrahydrofuran (200 mL), a 2.2 mol/L solution of diethyl azodicarboxylate in toluene (51 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate were added, the insoluble matter was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-(3,3-dimethyl-4-pentyn-1-yl)isoindoline-1,3-dione (F12, 7.1 g) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.B(O)(O)[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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]>[Cl:1][C:2]1[C:3]2[C:10]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3ccccc3c2)c2c(Cl)ncnc21
Yield: 26.2 %

Procedure:
A solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (19 mg, 0.065 mmol), naphthalen-2-yl-2-boronic acid (12.2 mg, 0.071 mmol), Na2CO3 (68.9 mg, 0.65 mmol) and PdCl2(dppf) (26.5 mg, 0.00325 mmol) in THF (3 mL) was heated to reflux overnight under an argon atmosphere. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield ZK102 (5 mg, 26% yield). ESI-MS (M+H)+ m/z calcd 294.1, found 294.3.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[N:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=[N:22]1>>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([C:25]2[N:21]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][O:15]3)[N:22]=[CH:23][CH:24]=2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Product: O=[N+]([O-])c1ccc(-c2ccnn2C2CCCCO2)cc1C(F)(F)F
Yield: 61.7 %

Procedure:
The title compound was prepared from 5-bromo-2-nitrobenzotrifluoride (5 g, 18.52 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.67 g, 20.37 mmol) using the method of Example 34(a). Reaction afforded 3.90 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.49-1.68 (m, 3H), 1.82 (m, 1H), 1.94 (m, 1H), 2.38 (m, 1H), 3.61 (m, 1H), 3.99 (d, 1H), 5.31 (m, 1H), 6.78 (d, 1H), 7.66 (d, 1H), 8.10 (m, 1H), 8.19 (m, 1H), 8.32 (d, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:18]=[C:19]([F:26])[C:20]2[CH:24]=[CH:23][S:22][C:21]=2[CH:25]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:18]=[C:19]([F:26])[C:20]4[CH:24]=[CH:23][S:22][C:21]=4[CH:25]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Fc1cc(Br)cc2sccc12
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cc(F)c3ccsc3c2)CCN1c1cnccc1C1CC1
Yield: 24.5 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 120 mg, 0.591 mmol) was reacted with 6-bromo-4-fluoro-benzo[b]thiophene (I-26d: 163.6 mg, 0.738 mmol), copper iodide (11.2 mg, 0.059 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (8.9 mg, 0.0591 mmol), potassium phosphate (375.9 mg, 1.7 mmol) and 1,4-dioxane (5 mL). Purification by column chromatography on silica gel (0.3% methanol in CHCl3) afforded 51.2 mg of the product (26% yield).