Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([CH3:28])[CH:22]=[CH:21]2.[I:29]I.O.NN>ClC1C=CC=CC=1.C1(C)C=CC=CC=1>[I-:29].[CH:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N+:13]4[CH:28]=[C:23]5[CH:22]=[CH:21][C:20]6[CH:19]=[C:18]([F:17])[CH:27]=[CH:26][C:25]=6[N:24]5[C:12]=4[CH:11]=[CH:10][C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cnc2ccc(C3CCCCC3)cc2c1
Reactant: II
Reactant: Cc1ccc2cc(F)ccc2n1
Agent: NN
Solvent: Cc1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: Fc1ccc2c(ccc3c[n+]4c5ccc(C6CCCCC6)cc5ccc4n32)c1
Product: [I-]

Procedure:
A mixture of 85.0 g. of 6-cyclohexylquinoline, 16.4 g. of 6-fluoroquinaldine, 150 ml. of toluene and 51.6 g. of iodine is stirred for 30 minutes at 20-25° C., then heated at 95°-100° C. for 6 days. The mixture is cooled, diluted with 300 ml. of chlorobenzene and treated dropwise with hydrazine hydrate until the dark-colored mixture becomes light tan. The precipitate is collected, washed with chlorobenzene and suspended in 400 ml. of cold methanol. The resulting solid 3-cyclohexyl-10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration and crystallized from dimethylformamide/methanol; m.p. ca 225° C.-235° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C.[CH:22]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])OCC>O>[CH2:30]([O:29][C:22]1([O:26][CH2:27][CH3:28])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)[CH3:31]
Reactant: O=C1CCCCC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC1(OCC)CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a round bottom flask 6 g (6.4 ml) Cyclohexanone, a pinch of p-toluene sulfonic acid and 10 ml absolute ethanol was taken. Stirred the mixture at R.T. for 5 min. Then add to it 18.12 g (20.3 ml) triethyl orthoformate and stir for 3 hr at R.T. Then distilled on rotavapour to get a thick mass. Add to it 30 ml water and extract with (25 ml×ethyl acetate, wash the organic layer with water, dried it by adding sodium sulfate and concentrate it on rotavapour to give a colorless liquid product.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([I:9])=[CH:7][N:8]=2)[CH2:3][CH2:2]1.[CH:10](Br)([CH3:12])[CH3:11]>>[CH:1]1([C:4]2[N:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([I:9])[N:5]=2)[CH2:3][CH2:2]1
Reactant: Ic1cnc(C2CC2)[nH]1
Reactant: CC(C)Br
Product: CC(C)n1cc(I)nc1C1CC1

Procedure:
The title compound, MS: m/e=277.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-cyclopropyl-5-iodo-1H-imidazole (example C) and isopropylbromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1/[C:5]/2=[N:17]\[S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19].[Cl-].[C:25]([O:29][C:30](=[O:33])[CH2:31][Zn+])([CH3:28])([CH3:27])[CH3:26].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C@@:5]2([CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])[NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19].[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C@:5]2([CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])[NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: CC(C)(C)[S@](=O)/N=c1/c2cc(Br)ccc2oc2cnc(Cl)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@]1(N[S@@](=O)C(C)(C)C)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Product: CC(C)(C)OC(=O)C[C@]1(N[S@@](=O)C(C)(C)C)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of (S,Z)-N-(7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (3000 mg, 7.25 mmol) in THF (25 mL) was slowly added 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in diethyl ether, 36.3 mL, 18.13 mmol) in an ice bath. The mixture was stirred at 0° C. for 25 mins, then 80 mL of saturated NH4Cl aqueous solution was added to quench the reaction. The reaction mixture was extracted with EtOAc (2×35 mL). The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude material as an orange solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 20% to 50% DCM/MeOH (90/10) in DCM. The fractions which contain mixture were repurified using 40 g Redi-Sep pre-packed silica gel column and eluting with a gradient of 0% to 20% to 50% DCM/MeOH (90/10) in DCM. The desired fractions were collected and concentrated to provide tert-butyl 2-((S)-7-bromo-3-chloro-5-((S)-1,1-dimethylethylsulfinamido)-5H-chromeno[2,3-c]pyridin-5-yl)acetate (isomer A, high Rf), and tert-butyl 2-((R)-7-bromo-3-chloro-5-((S)-1,1-dimethylethylsulfinamido)-5H-chromeno[2,3-c]pyridin-5-yl)acetate (isomer B, low Rf) as off-white solid. Isomer A: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (s, 9 H) 1.03 (s, 9 H) 3.42 (s, 2 H) 6.41 (s, 1 H) 7.15 (d, J=8.71 Hz, 1 H) 7.52 (dd, J=8.80, 2.35 Hz, 1 H) 7.79 (s, 1 H) 7.98 (d, J=2.45 Hz, 1 H) 8.37 (s, 1 H). Isomer B: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (s, 9 H) 1.04 (s, 9 H) 3.34 (s, 1 H) 3.42 (s, 1 H) 6.35 (s, 1 H) 7.16 (d, J=8.80 Hz, 1 H) 7.54 (dd, J=8.80, 2.45 Hz, 1 H) 7.77 (d, J=2.35 Hz, 1 H) 7.95 (s, 1 H) 8.35 (s, 1 H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=1.ClC1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O.[Cu]>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:4][C:1]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Cu]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Cl)cc1
Yield: 83.3 %

Procedure:
56 g (0.400 mol) of potassium carbonate and 5.6 g of purified copper are added to a lukewarm solution (≃60° C.) of 51.5 g (0.400 mol) of p-chlorophenol and 72 g (0.456 mol) of p-chloronitrobenzene in 40 ml of dimethylformamide and the mixture is then heated to the reflux temperature for 5 hours. The inorganic salts are removed by filtering the reaction mixture and the dimethylformamide is evaporated under reduced pressure. The residue is purified by crystallisation from methanol to give 83.2 g of a yellow beige powder.
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[C:6]1=[O:13])([CH2:3][CH3:4])[CH3:2].Cl.[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[NH:23][CH2:22][CH2:21]2>>[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[N:23]([C:7]1[C:6](=[O:13])[N:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:10]=[C:9]([Cl:11])[N:8]=1)[CH2:22][CH2:21]2
Reactant: CCC(C)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CCC(C)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 155-157° C.; 1H NMR (300 MHz, CDCl3): δ 6.90 (d, J=2.6 Hz, 1 H), 6.78 (s, 1 H), 6.76 (d, J=2.1 Hz, 1H), 4.99-4.87 (m, 1 H), 4.34 (t, J=7.7 Hz, 2 H), 3.76 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.74-1.65 (m, 2 H), 1.34 (d, J=7.0 Hz, 3 H), 0.89 (t, J=7.5 Hz, 3H); HRMS (ESI) calcd for C20H22N3O2BrCl (M+H)+: 412.0427; found m/z 412.0448.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[Cl:7].O1CCCC1.[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[Cl:7]
Reactant: CCOC(=O)C(=O)c1c(C)sc(Cl)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(O)c1c(C)sc(Cl)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a mixture of compound ethyl 2-(4-bromo-5-chloro-2-methylthiophen-3-yl)-2-oxoacetate (44b) (340 mg, 1.09 mmol), tetrahydrofuran (7 mL) and ethanol (1.7 mL) was added sodium tetraborohydride (37.2 mg, 0.98 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours. The mixture was quenched with hydrochloric acid 1N and extracted with ethyl acetate twice. The organic extract was washed with brine twice, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude alcohol (44c) as a colorless oil (335 mg, 1.07 mmol, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[S:16][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]=[C:33]=[O:34].O>C1COCC1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[NH:32][C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[S:16][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1)=[O:34]
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: COC(=O)c1cc(-c2cc(Oc3ccc(N)cc3)ccn2)cs1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]thiophene-2-carboxylate (500 mg, 1.53 mmol) in anhydrous THF (10 ml) was added 2-fluoro-5-methyl-phenylisocyanate (255 mg, 1.68 mmol). The mixture was stirred at room temperature for one hour and poured into 200 ml of water. The resulting precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3-5% MeOH/CHCl3 to give methyl 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylate as off-white solid. Yield: 560 mg, 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([OH:28])=O)[N:20]=1.[CH:32]([N:35](CC)[CH:36](C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CNC.C1COCC1>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([N:35]([CH3:36])[CH3:32])=[O:28])[N:20]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)O)n4)n3Cc3cccc(Cl)c3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)N(C)C)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.03 h

Procedure:
To a solution of 3-{3-[6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl]-1H-pyrazol-1-yl}propanoic acid (8.0 mg, 0.018 mmol, from Step 6) in DMF (0.25 mL) was added N,N-diisopropylethylamine (13 μL, 0.074 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (12 mg, 0.033 mmol, Aldrich). After 2 minutes, 2.0 M dimethylamine in THF (0.074 mL, 0.15 mmol, Aldrich) was added. After 15 minutes, the reaction was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (5.5 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)O[C:6](=[O:7])[C:5]2=[CH:12][C:13]=1[Cl:14].[H-].[Na+].CSC(=N)[NH:20][S:21]([CH2:24]Cl)(=[O:23])=[O:22].C[N:28]1CCCC1=O>>[Cl:14][C:13]1[CH:12]=[C:5]2[C:4](=[CH:3][C:2]=1[Cl:1])[N:10]=[C:9]1[NH:20][S:21](=[O:22])(=[O:23])[CH2:24][N:28]1[C:6]2=[O:7]
Reactant: CN1CCCC1=O
Reactant: CSC(=N)NS(=O)(=O)CCl
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Product: O=c1c2cc(Cl)c(Cl)cc2nc2n1CS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred slurry of 4,5-dichloroisatoic anhydride (11.54 g, 50 mmol) in N-methyl-2-pyrrolidinone (50 ml) under nitrogen is added sodium hydride (2.05 g of 60% oil dispersion, 52 mmol). The mixture is stirred for 30 min at room temperature, and to the resulting solution is added S-methyl-N-(chloromethanesulfonyl)-isothiourea (11.0 g, 55 mmol). The mixture is stirred under nitrogen at 80° C. for 18 hr, then worked up as in Example 4 above. Recrystallization from DMF provides the title compound as a white solid, mp >300° C. (4.69 g, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[OH:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH:11]([O:12][S:31]([CH3:30])(=[O:33])=[O:32])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc(Br)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
Dissolved the product from Example 39B (3.68 g, 10.05 mmol) in dichloromethane (167 mL) and cooled the solution in an ice bath followed by the addition of triethylamine (4.20 mL, 30.1 mmol) and methanesulfonyl chloride (1.96 mL, 25.1 mmol) dropwise. After stirring for 15 min, the solution was concentrated to a solid (5.25 g, 100%) that was used directly in the next reaction.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[CH3:17][C:18]1[N:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([C:24](=[NH:25])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)[N:23]=1
Reactant: Cc1cccc(C#N)n1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (4.2 g, 20.3 mmol) in toluene (100 ml) at 0° C., was added trimethylaluminum (2M solution in toluene, 12 ml, 24 mmol) over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 6-methyl-2-cyanopyridine (3.6 g, 30.5 mmol) in toluene (100 ml) was added over 10 minutes and the mixture was heated to 85-90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with hexane and ethyl acetate (1000 ml) and filtered. The white solid (5.1 g, 87%) was used in the next reaction without further purification. Anal. Calc'd. for C14H16N3SClO20.2H2O: C, 51.05, H, 5.02, N, 12.76. Found: C, 50.97, H. 4.78, N, 12.80.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[C:10]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of compound 6 (0.62 g, 2.3 mmol) in THF (50 mL) was treated with thionyl chloride (0.94 mL), stirred at room temperature for 4 h, and evaporated to dryness. The residue was dissolved in THF (50 mL) and treated with aniline (0.58 mL, 6.4 mmol) and diisopropylethylamine (1.12 mL, 6.4 mmol). The reaction mixture was stirred for 4 h, concentrated, dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL), dried with sodium sulfate, and concentrated. The crude residue of compound 7 then was purified by flash chromatography (5% methanol in dichloromethane).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:17][CH:1]3[C:10]4[C:5]([CH:4]=[CH:3][N:2]3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]2=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:14][CH:13]=1
Reactant: c1ccc2cnccc2c1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc(C2OC3c4ccccc4C=CN3c3ccccc32)cc1
Yield: 82 %

Procedure:
Following the general procedure, treatment of isoquinoline (0.129 g, 120 μL, 1.0 mmol) and 4-bromobenzaldehyde (0.278 g, 1.5 mmol) with 2-(trimethylsilyl)phenyl trifluoro-methane sulfonate (0.308 g, 292 μL, 1.2 mmol) in the presence of KF (0.140 g, 2.4 mmol) and 18-crown-6 (0.634 g, 2.4 mmol) in THF (4.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=93/07) of the crude reaction mixture afforded 6-(4-bromophenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline as inseparable mixture of diastereomers as a yellow solid (0.314 g, 82% yield, dr determined by 1H NMR analysis of crude reaction mixture is 3:2).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:25]1[CH:26]=[C:27]([CH2:34][OH:35])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]>C(#N)C>[OH:35][CH2:34][C:27]1[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:25]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[CH:26]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(CO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (7.09 g, 32.1 mmol) and DIPEA (15 mL, 88 mmol) in ACN (50 mL) was added (3-fluoro-4-nitrophenyl)methanol (5 g, 29.2 mmol). The reaction was stirred overnight at 80° C. The reaction mixture was concentrated, loaded onto a silica-gel pre column, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-4-(5-(hydroxymethyl)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide as an orange foam (7.0 g, 71.4% yield). MS, m/z (C17H25N3O4): calcd, 335.2. found, 336.0 [M+H].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.[NH2:11][NH2:12]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:11][NH2:12])=[O:9])[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCOCC1
Reactant: NN
Solvent: CO
Product: NNC(=O)C1CCOCC1
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A solution of methyl tetrahydro-2H-pyran-4-carboxylate (1.44 g, 10.0 mmol) in methanol (50 mL) was stirred at 50° C. To the reaction mixture, hydrazine.monohydrate (0.675 g) was added, followed by stirring at the same temperature for 2 hours, after completion of the reaction, the reaction mixture was concentrated and diluted with methylene chloride, the solution was then washed with saturated sodium bicarbonate aqueous solution and saturated brine, and the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to afford 952 mg of the title compound (yield 66.1%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[C:21]([Zn]C#N)#[N:22]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([C:21]#[N:22])[CH:18]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.355 g, 0.998 mmol) was combined with dicyanozinc (0.100 g, 0.852 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.100 mmol) in DMF (3 mL) and heated at 120° C. for 25 min in a microwave reactor under an inert atmosphere. The reaction mixture was diluted with EtOAc, washed twice with saturated aqueous NaHCO3 and twice with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in CH3OH and gravity filtered through a StratoSpheres™ PL-Thiol MP SPE+ cartridge. The filtrate was concentrated to dryness and purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give 5-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-1,3-benzenedicarbonitrile (0.200 g, 0.663 mmol, 66.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 7.91 (s, 2H), 7.46-7.57 (m, 2H), 3.77 (s, 2H), 1.90 (br. s., 2H). LC-MS (ES+) m/z 302.27, 304.19 [M+H].
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]2[C:17](=[CH:18][C:19]([NH:27][C:28]([C:30]3[C:31]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=4)=[N:32][CH:33]=[CH:34][CH:35]=3)=[O:29])=[CH:20][CH:21]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:25][C:23]1([CH3:26])[C:22]2[C:17](=[CH:18][C:19]([NH:27][C:28](=[O:29])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][C:31]=3[NH:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=3)=[CH:20][CH:21]=2)[CH2:16][NH:15][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccc(F)cn3)ccc2C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3ccc(F)cn3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 ml of TFA was added to a solution of 7-({2-[(5-fluoro-pyridin-2-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.20 g, 0.40 mmol) in 2.5 ml of CH2Cl2. The mixture was stirred at RT for 1 h. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (2 to 5% of MeOH in CH2Cl2 with 2% of NH4OH). The titled compound was obtained as an off-white solid. MS: (ES+) 406.1 (M+H). Calc'd. for C23H24FN5O—405.47.