Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:14])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=[O:13])[C:2]1=2.[OH-].[Na+].C1(C)C=CC(S(O[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=O)=O)=CC=1>[Zn].C(O)C>[CH2:5]([O:14][C:6]1[C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([O:13][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27])=[C:2]2[S:1][CH:5]=[CH:4][C:3]=12)[CH2:4][CH2:3][CH2:2][CH2:12][CH2:11][CH2:7][CH3:6]
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Reactant: CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: CCCCCCCCOc1c2ccsc2c(OCCCCCCCC)c2ccsc12
Yield: 62 %

Procedure:
1.0 g (4.5 mmol) of benzo[1,2-b:4,5-b′]dithiophene-4,8-dione was mixed with 0.65 g (10 mmol) of zinc dust in a flask. Then, 4 ml of ethanol and 15 ml of 20% NaOH was added and the mixture was refluxed for 1 h. 4.3 mL octyl p-toluenesulfonate was added in portions with stirring until the color changed to red. The resulting precipitate was filtered, the filtrate was diluted with 100 mL water and extracted with 100 mL chloroform. The organic extraction was dried with anhydrous sodium sulfate and evaporated in vacuo. Column chromatography on silica gel using dichloromethane and hexanes mixed solvents yielded the pure title compound as a white solid (1.24 g, 62%). 1HNMR (CDCl3): δ 0.88-0.91 (6H, t, J=7 Hz), 1.31-1.38 (16H, m), 1.54-1.58 (4H, m), 1.84-1.89 (4H, m), 4.26-4.29 (4H, J=7 Hz), 7.36-7.37 (2H, d, J=6 Hz), 7.47-7.48 (2H, d, J=6 Hz).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:35])=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([C:27]4[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=4[CH3:35])[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(Cl)cc1N1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-chloro-2-methyl-phenyl)-piperazine The crude product was converted to the free base, yield 26%. White crystals; HPLC-MS:m/z=492(M+H) at Rt=5.5 min.; IR (KBr): ν 1722 (C═O) cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[O-:14].[K+].Br[CH2:17][CH2:18][OH:19].CN(P(N(C)C)N(C)C)C.Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[O:14][CH2:17][CH2:18][OH:19]
Reactant: OCCBr
Reactant: COc1cc([N+](=O)[O-])cc(OC)c1[O-]
Agent: CN(C)P(N(C)C)N(C)C
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCCO

Procedure:
A slurry of potassium 2,6-dimethoxy-4-nitrophenolate [Collins, R. P. and Davis, M. J. Chem. Soc. (1961), 1986] (38 g, 160 mmol) in DMF (600 ml) was treated with 2-bromoethanol (25 ml, 353 mmol) and hexamethylphosphorus triamide (31 ml, 176 mmol) and the reaction heated at 115° for 6 h. After cooling, the reaction was poured onto 1M hydrochloric acid (1.5 l) and extracted with ethyl acetate (5×500 ml). The organics were washed with 1M sodium hydroxide (4×700 ml), brine (200 ml) and drfied (MgSO4). Concentration in vacuo gave 3,5-dimethoxy-4-(2-hydroxyethoxy)nitrobenzene as an off white solid (31 g) δH (CDCl3) 7.52 (2H, s), 4.21 (2H, t, J 2.9 Hz), 3.94 (3H, s), 3.76 (2H, m) and 2.94 (1H, br s). MS (ES+) 266 (MNa+, 50%), 244 (MH+, 100%). A mixture of this nitrobenzene (750 mg, 3.16 mmol) and 10% palladium on carbon (75 mg) in ethanol (50 ml) was degassed and then subjected to an atmosphere of hydrogen (balloon) for 16 h. at 200. Dichloromethane was added and the solution filtered and solvent removed in vacuo to give 3,5-dimethoxy-4-(2-hydroxyethoxy)aniline as a grey solid (620 mg) after trituration with diethyl ether. δH (CDCl3+DMSO) 5.84 (2H, s), 3.87-3.84 (2H, m), 3.64 (6H, s) and 3.52-3.49 (2H, m). MS (ES+) 214 (MH+, 100%.
Reaction SMILES: [CH2:1](P(Cl)(Cl)=O)[P:2]([Cl:5])([Cl:4])=[O:3].O[C:11]1[CH:24]=[CH:23][C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.N1C=CC=CC=1.O>C(Cl)Cl>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:1][P:2]([Cl:5])([Cl:4])=[O:3])=[CH:19][CH:18]=1)(=[O:16])[C:14]1[CH:23]=[CH:24][CH:11]=[CH:12][CH:13]=1
Reactant: O=P(Cl)(Cl)CP(=O)(Cl)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(CP(=O)(Cl)Cl)cc1

Procedure:
A degradable linking agent is formed by reacting methylenebis(phosphonic dichloride) (1 eq) with 4-hydroxybenzophenone (2 eq) in anhydrous DCM using pyridine (2.5 eq) as a base. The resulting product can be converted into its salt to increase water solubility.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CN(C)CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOCCOc1cc(C#N)ccn1
Temperature: 50 °C
Yield: 105.8 %

Procedure:
To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50° C. for 2 h. The warm sodium alkoxide solution was added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After the addition, the reaction mixture was heated to 70° C. for 2 h, then DMF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light yellow oil (5.6 g). MS: 236 (M+1). Calc'd. for C12H17N3O2−235.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]COC)=[C:7]([Cl:13])[C:6]([O:14][CH3:15])=[C:5]([O:16]COC)[C:4]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:30]([O:31]COC)=[C:29]([O:35][CH3:36])[CH:28]=[C:27]([O:37]COC)[C:26]=1[O:41][CH3:42].Cl.C(OCC)(=O)C.CCCCCC>C(O)C.O1CCCC1.C(#N)C.C(OCC)(=O)C>[CH3:15][O:14][C:6]1[C:5](=[O:16])[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[C:30](=[O:31])[C:29]([O:35][CH3:36])=[CH:28][C:27](=[O:37])[C:26]=2[O:41][CH3:42])=[C:3]([O:2][CH3:1])[C:8](=[O:9])[C:7]=1[Cl:13]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(Cl)c(OC)c2OCOC)c1OC
Agent: Cl
Solvent: CC#N
Solvent: CCO
Solvent: C1CCOC1
Product: COC1=CC(=O)C(OC)=C(CCCCCC2=C(OC)C(=O)C(Cl)=C(OC)C2=O)C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
219 Milligrams (0.35 mM) of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-chlorophenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]pentane was dissolved in 5 ml of a mixed solvent of ethanol-tetrahydrofuran (1:1), to this solution was added 0.5 ml of a mixed solvent of ethanol-tetrahydrofuran (1:1) containing 20% of hydrogen chloride under an atmosphere of argon gas at a room temperature, then the reaction mixture was stirred for 2 hours at 60° C. The solvent was removed under reduced pressure, to the residue was added 5 ml of benzene, and the mixture was again treated under reduced pressure to remove the hydrogen chloride. The residue obtained was dissolved in 20 ml of acetonitrile, further added 1.5 ml of acetonitrile solution of complex of Cu4Cl4O2 (CH3CN)3 (which was prepared by adding 1 g of cuprous chloride in 25 ml of acetonitrile under bubbling oxygen gas), and the reaction mixture was stirred for 1 hour under oxygen gas stream conditions. The solvent was removed under reduced pressure, the residue obtained was dissolved in 30 ml of ethyl acetate, then the organic layer was washed three times with 10 ml of water, then washed once with 10 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, then concentrated under a reduced pressure. The residue obtained was treated by means of a silica gel thin layer chromatography (adsorbent: Silica gel 60 F254, E. Merck A. G.-thickness: 1 mm, developing solvent: 50% ethyl acetate-n-hexane) to obtain 107 mg of 2,5-dimethoxy-3-chloro-6-[5-(2,5-dimethoxy-1,4-benzoquinon-3-yl)pentyl]-1,4-benzoquinone. Orange powdery substance.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27].NC(N)=O>>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Agent: NC(N)=O
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Br)cnn1C

Procedure:
reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate in the presence of a urea-forming solvent to form 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)([OH:13])=[O:12].CC1C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]([OH:13])=[O:12])=[CH:19][CH:18]=2)(=[O:21])=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: N#Cc1ccc(C=NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In a similar manner to Example 2, 1.25 g (9 mmol) of 4-cyanobenzaldehyde, 1.91 g (9 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of chlorobenzene under nitrogen were heated for 18 hours to give 2.58 g (86%) of SULF-7 as a white powder: IR (Nujol) 3400-2400 (br), 2224, 1682, 1605, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std)δ 9.35 (s, 1), 8.3-7.8 (m, 8).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]5[NH:37][CH2:38][CH2:39][C:32]=45)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[NH:37]1[C:33]2=[N:34][CH:35]=[CH:36][C:31]([CH2:30][NH:29][C:24]3[N:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]([NH:20][C:12]3[CH:11]=[C:10]4[C:15]([C:16]([CH3:19])([CH3:18])[CH2:17][NH:8][CH2:9]4)=[CH:14][CH:13]=3)=[O:22])=[C:32]2[CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc2C(C)(C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7-({2-[(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.070 g), HCl (4N, 3.0 mL) and dioxane (4.0 mL) was stirred at RT for overnight. Sat'd NaHCO3 was added until the bubbling stopped. The aqueous phase was extracted with CH2Cl2 3 times. The combined organic phases were dried over Na2SO4 and evaporated to yield a tan colored residue as a crude product, which was chromatographed through HPLC. The fractions were collected and the solvent was evaporated. The residue was treated with NaHCO3 and the solvent was evaporated. The residue was washed with H2O to remove any inorganics to afford 2-[(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-amino]-N-(4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)/[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])/[C:9]/2=[C:4]1\[CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=2)[C:6]([CH3:8])([CH3:7])[O:5]\1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1c1ccc(C=O)cc1
Temperature: 65 °C
Yield: 51.5 %

Procedure:
To a mixture of 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (6.5 g, 20 mmol), 4-formyl phenyl boronic acid (3.6 g, 24 mmol) in THF (250 mL), was added a solution of potassium carbonate (27.6 g, 200 mmol) in water (25 mL). The resulting mixture was deoxygenated with nitrogen, and palladium(0) tetrakis(triphenylphosphine) (1.15 g, 1.0 mmol, 5 mol %) then added. The reaction mixture was heated at 65° C. for 20 hours and then it was allowed to cool to room temperature. Ethyl acetate (800 mL) was added. The organic phase was washed with water (200 mL×2), dried over sodium sulfate and evaporated to give crude product. The purification first by column (SiO2) chromatography (5% CH3OH/CH2Cl2) and then by titration with ethyl acetate led to 4-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-2,2-dimethyl-2,5-dihydro-furan-3-yl}-benzaldehyde as a deep red solid (3.6 g, yield 51.5%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH2:17][CH2:18][CH2:19]Cl)=[CH:11][CH:12]=2)[CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>CS(C)=O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][C:10]([O:16][CH2:17][CH2:18][CH2:19][NH:29][C:26]4[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)=[CH:11][CH:12]=3)[CH:7]=2)=[CH:25][CH:24]=1
Reactant: ClCCCOc1ccc2ccc(OCCCCl)cc2c1
Reactant: COc1ccc(N)cc1
Solvent: CS(C)=O
Product: COc1ccc(NCCCOc2ccc3ccc(OCCCNc4ccc(OC)cc4)cc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of 2,7-bis(3-chloropropyloxy)naphthalene (1 gm, 0.003 mole) and p-anisidine (1.17 gm, 0.005 mole) were taken in 60 ml dry DMSO. It was refluxed at 140° C. for 12 hrs the completion of the reaction was checked by TLC. The reaction mixture was poured into distilled water (80 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was further crystallized by benzene hexane to get the desired compound as solid, m.p. 127° C., (yield 1.34 gm, 89%).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.[CH3:13][C:14]1[CH:18]=[C:17]([CH2:19][OH:20])[S:16][N:15]=1.C(N(CC)CC)C.O>C(#N)C>[CH3:13][C:14]1[CH:18]=[C:17]([CH2:19][O:20][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[S:16][N:15]=1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: Cc1cc(CO)sn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1cc(COC2=NS(=O)(=O)c3ccccc32)sn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.3 %

Procedure:
In 8 ml of acetonitrile were dissolved 0.78 g (3.88 mmol) of 3-chloro-1,2-benzoisothiazole 1,1-dioxide and 0.50 g (3.88 mmol) of (3-methylisothiazol-5-yl)methanol. To the resulting solution was dropwise added 0.51 g (5.0 mmol) of triethylamine, followed by stirring at room temperature for 5 hours to give rise to a reaction. After the completion of the reaction, 16 ml of water was added. The resulting crystals were obtained by filtration and washed with water and isopropyl alcohol to obtain 0.30 g (yield: 26%) of 3-(3-methylisothiazol-5-ylmethoxy)-1,2-benzoisothiazole 1,1-dioxide as a light brown powder (melting point: 202 to 204° C.)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1.[F:14][C:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:17][C:16]=1[C:30]1[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[F:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[CH:18]=[CH:17][C:16]=1[C:30]1[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1
Reactant: Clc1ccccc1-c1cnccn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Product: Nc1cnc(-c2ccc(-c3ccccc3-c3cnccn3)cc2F)cn1
Temperature: 45 °C

Procedure:
2-(2-Chlorophenyl)pyrazine (58 mg, 0.31 mmol), 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine (88 mg, 0.28 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (4.4 mg, 0.0060 mmol) were placed into a sealable 5 mL vial equipped with a stir-bar. The vial was sealed, evacuated and backfilled with argon three times. To this vial was added separately deoxygenated THF (0.56 mL) and K3PO4 (1.1 mL, 0.5 M). The vial was then heated at 45° Celsius for 1 hour before cooling to rt diluting with brine (5 mL), and extracting with EtOAc (1×5 mL, 3×10 mL). The combined organic extracts were then dried with sodium sulfate, filtered, and concentrated to dryness. The crude product was purified via FCC to provide the title compound. MS (ESI): mass calcd. for C20H14FN5, 343.12; m/z found, 344.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.65-8.59 (dd, J=2.6, 1.6, 1H), 8.47-8.42 (d, J=2.6, 1H), 8.33-8.31 (dd, J=2.2, 1.4, 1H), 8.31-8.29 (d, J=1.5, 1H), 8.04-8.02 (d, J=1.5, 1H), 7.79-7.73 (m, 1H), 7.72-7.69 (m, 1H), 7.64-7.53 (m, 3H), 7.11-6.87 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.C([N:24](C(C)C)CC)(C)C.[OH-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[C:7]([C:8]([NH2:24])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:5]=[C:4]([S:19][CH3:20])[N:3]=1
Reactant: CSc1nc(C)c(C(=O)O)c(Nc2cccc(C)c2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nc(C)c(C(N)=O)c(Nc2cccc(C)c2)n1
Reaction time: 0.33 h
Yield: 60.5 %

Procedure:
To a solution of 4-methyl-6-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinecarboxylic acid (1.71 g, 5.90 mmole) in DMF (40 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uroniumhexafluoro phosphate (4.88 g, 12.8 mmol) and diisopropylethylamine (3.83 g, 29.6 mmol). The reaction mixture was stirred for 10 min before ammonium hydroxide (7.2 ml of 28%) was added. The mixture was stirred for additional 20 min and DMF was removed under vacuum. The residue was partitioned between ethyl acetate and water. The insoluble product was collected by filtration and dried under vacuum (0.54 g). The organic phase was separated, washed with 1N NaOH, water and dried over MgSO4. The solvent was removed under vacuum to give additional product (1.03 g) which was combined with the previously obtained precipitated product (1.27 g in total, 74% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:25]([CH3:37])=[N:26][C:27]2[C:32]([C:33]=1C(O)=O)=[CH:31][CH:30]=[CH:29][CH:28]=2>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:24]1[C:25]([CH3:37])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2
Reactant: COc1cc2c(Cl)ccnc2cc1NCCN1CCOCC1
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1NCCN1CCOCC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
(4-Chloro-6-methoxy-quinolin-7-yl)-(2-morpholin-4-yl-ethyl)-amine (53 mg), 3-hydroxy-2-methyl-quinolin-4-carboxylic acid (126 mg), and 4-dimethylaminopyridine (200 mg) were suspended in o-dichlorobenzene (8 ml). The suspension was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (12 mg, yield 16%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:22]([O:23][CH2:24][C@@H:25]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:21][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[C:12]3[C:17]([C:8]=2[CH:7]=1)=[CH:16][CH:15]=[N:14][C:13]=3[CH3:18])=[CH2:5])C.Cl.O1CCOCC1>>[C:4]([C:6]1[C:22]([O:23][CH2:24][C@@H:25]([NH2:30])[CH2:26][CH:27]([CH3:28])[CH3:29])=[CH:21][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[C:12]3[C:17]([C:8]=2[CH:7]=1)=[CH:16][CH:15]=[N:14][C:13]=3[CH3:18])(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
(S)-tert-Butyl (1-((9-(1-ethoxyvinyl)-4,6-dimethyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (200 mg, 0.392 mmol) was treated with hydrochloric acid in 1,4-dioxane (981 μL, 3.92 mmol) at 0° C. The reaction mixture was allowed to stir at RT for 2 h and then evaporated to dryness. The crude material was neutralized with aqueous 10% NaHCO3 and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated which afforded (S)-9-acetyl-8-((2-amino-4-methylpentyl)oxy)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.11 g, 0.164 mmol, 42% yield) as brown solid. The material was carried on without further purification. LC/MS (ESI) m/e 382.2 [(M+H)+, calcd for C22H28N3O3, 382.2]; LC/MS retention time (method E): tR=0.78 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5]P(=O)(OCC)OCC.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[CH:5]=[CH:38]/[C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=Cc1cccnc1
Reactant: CCOP(=O)(Cc1cccc(Br)c1)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(/C=C/c2cccnc2)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To diethyl 3-bromobenzylphosphonate (Kennedy, G. Perboni, A. D. Tetrahedron Lett. 1996, 37, 7611-7614; 1.91 g, 6.22 mmol) in dimethylformamide (20 mL) was added sodium methanolate (0.672 g, 12.44 mmol) followed by 18-crown-6 (0.658 g, 2.488 mmol) and nicotinaldehyde (0.666 g, 6.22 mmol). The reaction mixture was heated to 120° C. for 2 h at which time the heating bath was turned off and the reaction mixture was allowed to reach ambient temperature over 18 h. The mixture was poured into water and extracted with 3×75 mL ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to 1.7 g amber liquid which was loaded onto a 90 g silica gel cartridge and eluted with 5 to 60% ethyl acetate/hexanes over 1300 mL. The major spot (Rf=0.45; 50% ethyl acetate/hexanes; UV) was collected and concentrated to 939 mg as a colorless oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.72 (1H, d, J=1.83 Hz), 8.50 (1H, dd, J=4.73, 1.68 Hz), 7.81 (1H, dt, J=8.01, 1.95 Hz), 7.67 (1H, t, J=1.68 Hz), 7.37-7.46 (2H, m), 7.29 (1H, dd, J=7.93, 4.88 Hz), 7.20-7.25 (1H, m), 7.07 (2H, s).