Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([C:22]([OH:24])=[O:23])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:25](=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([C:22]([O:24][CH3:25])=[O:23])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2c1COC
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)OC)cc3c2c1COC
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
202 mg of 3-ethoxycarbonyl-4-methoxymethyl-β-carboline-6-carboxylic acid is combined in 15 ml of ethanol and 5 ml of water with 206 mg of cesium carbonate in 1.5 ml of water and stirred until a clear solution is obtained. The solution is then evaporated to dryness, taken up in 10 ml of dimethylformamide, 0.14 ml of methyl iodide is added, and the mixture is agitated at room temperature for 3 hours. After evaporation, the mixture is distributed in methylene chloride/saturated sodium chloride solution. The organic phase is dried, filtered, concentrated, and chromatographed over silica gel with methylene chloride/ethanol=6:1 as the eluent. After recrystallization of the corresponding fractions from ethanol/hexane, 92 mg of 6-methoxycarbonyl-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](S(C)=O)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])[N:25]=2)[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:1][C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=4)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH2:40][C:41]([OH:43])([CH3:42])[CH3:44])[N:25]=2)[CH2:21][CH2:22]1
Reactant: N#Cc1ccc(N)cc1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a solution of 4-aminobenzonitrile (16.34 mg, 0.138 mmol) in THF (277 μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 min. To the reaction mixture cooled back to −78° C., 1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for additional 1 h. According to LC/MS, the reaction was complete. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 min] followed by Biotage silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (16 mg, 28%).
Reaction SMILES: C(N[C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)C.[CH:15]([OH:17])=O.[CH2:18]([N:20](CC)CC)[CH3:19]>>[CH:15]([NH:20][CH2:18][CH2:19][C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:17]
Reactant: O=CO
Reactant: CCNc1cccc2c1CCCCC2
Reactant: CCN(CC)CC
Product: O=CNCCc1cccc2c1CCCCC2
Temperature: 25 °C

Procedure:
1-Ethylamino-benzocycloheptane (1 g, 5.3 mmol) was treated with formic acid (1.22 ml, 32 mmol) and triethylamine (1 ml, 7.2 mmol) and the mixture was heated under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the mixture was partitioned between diethyl ether (165 ml) and 5% aqueous NaHCO3 (100 ml). The organic layer was separated, dried (Na2SO4) and evaporated to a brown oil (1.06 g, 93%)
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[S:7])[CH2:2][CH2:3][CH3:4].[CH3:21][I:22]>CC(C)=O>[IH:22].[CH3:21][S:7][C:6](=[N:5][CH2:1][CH2:2][CH2:3][CH3:4])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CCCCNC(=S)Nc1ccccc1N1CCOCC1
Reactant: CI
Solvent: CC(C)=O
Product: CCCCN=C(Nc1ccccc1N1CCOCC1)SC
Product: I

Procedure:
A mixture of 1-(n-butyl)-3-(2-morpholinophenyl)thiourea (5.8 g) and methyliodide (3.1 g) in acetone (25 ml) was heated at reflux for 4 hours to yield 2-methyl-3-(n-butyl)-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide as a colourless solid m.p. 154°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][NH:6][C:7]([NH:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][N:6]([CH2:30][CH3:31])[C:7]([NH:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11])=[O:8]
Reactant: CCI
Reactant: CC(C)(NC(=O)NOc1cc(Cl)cc(Br)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Oc1cc(Cl)cc(Br)c1)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
2.89 g of 1-(3-bromo-5-chlorophenoxy)-3-(2-phenylpropan-2-yl)urea was dissolved in 30 ml of N,N-dimethyl formamide. The resulting solution was added to a mixture of 5.18 g of potassium carbonate and 1.17 g of iodoethane, followd by stirring for one night at room temperature. Ethyl actate was then added to the susulting solution. The resulting mixture was washed with ammonium chloride, and the organic layer was dried with magnesium sulfate. After filtration, the solvent was distilled off. The resulting residues was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=5:1) to obtain the target compound of 1-(3-bromo-5-chlorophenoxy)-1-ethyl-3-(2-phenylpropan-2-yl)urea (2.86 g, yield: 92%).
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])C=1.[O:13]([C:20]1[CH:27]=[CH:26]C(CN)=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[ClH:28]>CN(C=O)C>[Cl:28][C:17]1[CH:16]=[CH:15][C:14]([OH:13])=[C:19]([CH:18]=1)[C:6]([NH:8][CH2:9][C:10]1[CH:22]=[CH:21][C:20]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:27][CH:26]=1)=[O:7]
Reactant: Cl
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Oc2ccccc2)cc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of 5-chlorocsalicyclic acid in anhydrous DMF (5 mL) was added CDI (0.167 g, 1.043 mmol), at 25° C. under nitrogen atmosphere. The reaction mixture was stirred for another 2 h at 25° C. To the above reaction mixture 4-phenoxy benzylamine was added and stirring continued overnight. At the end of this period 2N HCl (20 mL) was added and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate layer was washed with water (2×30 mL), dried (Na2SO4), filtered and solvent was evaporated. The resulting crude material was chromatographed over silica gel using mixture of ethyl acetate and hexanes (3:7) to give title product (0.121 g, 27%). 1H NMR (CDCl3) δ 4.60 (d, 2H), 6.44 (bs, 1H), 6.90-7.37 (m, 12H), 12.21 (s, 1H),
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[CH:20]=[C:19]([C:30]([OH:32])=[O:31])[N:18]=2)[O:9][N:8]=1.S(=O)(=O)(O)O.[CH3:38]O>>[CH3:38][O:31][C:30]([C:19]1[N:18]=[C:17]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:11]=2)[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[CH:20]=1)=[O:32]
Reactant: Cc1cc(Nc2cc(C(=O)O)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Yield: 51 %

Procedure:
A mixture of 2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-6-yl carboxylic acid (Method 43) (1.73 g, 4.0 mmol), methanol (300 ml) and 98% sulphuric acid (1 ml) was heated at reflux for 18 hours. The volatiles were removed by evaporation, the residue dissolved in water and the pH of the resulting solution adjusted to pH 12 with 10M sodium hydroxide. The aqueous solution was extracted with DCM and purified by chromatography on silica gel, eluting with DCM/methanol (100:0 increasing in polarity to 90:10) to give the title compound (904 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[N:24]([C:27](OCC)=O)=C=S.[Cl-].O[NH3+].C([N:38](CC)C(C)C)(C)C>CO.C(O)C.CS(C)=O>[NH2:38][C:27]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:10]=[C:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14]=3[CH3:15])=[CH:6][N:7]2[N:24]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc(N)nc1
Reactant: CCOC(=O)N=C=S
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(N)nn2c1
Yield: 81.5 %

Procedure:
In the same manner as in Example 17-1 and using tert-butyl {3-[(6-aminopyridin-3-yl)oxy]-4-methylphenyl}carbamate (1.69 g, 5.35 mmol), DMSO (5 mL), ethyl isothiocyanatoformate (843 mg, 6.42 mmol), ethanol (20 mL), methanol (20 mL), hydroxylammonium chloride (2.43 g, 35.0 mmol) and N,N-diisopropylethylamine (4.35 mL, 25.0 mmol) as starting materials, the title compound (1.55 g, 87%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[CH:21]([F:23])[F:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:7]=1.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[CH:21]([F:22])[F:23])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:24][C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=2)=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)F)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)F)cc1=O

Procedure:
115 mg (0.32 mmol) of 2-{5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. After work-up, the crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 79 mg (46% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)cc1Cl)Nc1ccccc1
Temperature: 25 °C

Procedure:
2,4-Dichlorophenylacetyl chloride (0.075 mol) was added dropwise over 1 h to a stirred solution of aniline (6.8 g) and triethylamine (7.6 g) in dry ether (200 ml) at 0°-5° C. The reaction mixture was allowed to warm up to room temperature overnight. It was then poured into iced water. An oily layer separated out and gradually solidified. This was recrystallised from diisopropyl ether to give 2-(2,4-dichlorophenyl)acetanilide, m.p. 145.6°-146.5° C.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.F[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: Fc1ccccn1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(c4ccccn4)CC3)cc2)cc1NCc1cccc(F)c1F
Temperature: 125 °C
Reaction time: 24 h

Procedure:
The mixture of 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (55 mg, 0.11 mmol), DIEA (0.1 mL, 0.55 mmol), 2-fluoropyridine (110 mg, 1.10 mmol) in 3 mL NMP was stirred in a sealed tube at 125° C. for 1 day. It was acidified with TFA and subjected to reverse phase preparative HPLC to isolate the title compound. MS found for C29H28F2N6O as (M+H)+ 515.4. UV: λ=249, 306 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 8.00-7.94 (2H, m), 7.39 (1H, d, J=9.2 Hz), 7.36 (2H, dt, J=8.0; 2.0 Hz), 7.25 (1H, m), 7.18 (1H, m), 7.14-7.07 (3H, m), 6.94 (1H, t, J=7.2 Hz), 5.79 (1H, s), 4.55 (2H, s), 4.36 (2H, m), 3.38 (2H, m), 3.03 (1H, m), 2.08 (2H, m), 1.87 (2H, m) ppm.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][C:20]=1[C:31]([F:34])([F:33])[F:32]>>[ClH:1].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[C:31]([F:33])([F:32])[F:34]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3ccc(Cl)c(C(F)(F)F)c3)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-3-tri-fluormethyl-phenyl)-piperazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:22][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]=2[CH:13]=[C:12]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:11]=1)=[CH:3][C:2]([C:29]1[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: C1COCCN1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(N2CCOCC2)nc1F

Procedure:
The titled compound was synthesized by steps analogous to those described in Method CC4 above using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′ oxazol]-2′-amine (prepared as described in Method BB33), 2-fluoropyridin-3-ylboronic acid, and morpholine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH2:47][CH3:48]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:44][CH2:45][O:46][CH2:47][CH3:48])[C:18](=[O:28])[N:17]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCCBr
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2COC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCOCC)c(=O)n2COC(=O)C(C)(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
4-[7-(2-Butynyl)-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (40 mg) and potassium carbonate (17 mg) were dissolved in N,N-dimethylformamide (1.5 ml), and 2-bromoethylethyl ether (14 μl) was added to the solution. The mixture was stirred at 60° C. for 5 hours, diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After removing the solvent by distillation, the residue was purified by silica gel column chromatography to give 4-[7-(2-butynyl)-3-(2,2-dimethylpropionyloxymethyl)-1-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester from the elution fraction of hexane-ethyl acetate (1:1). The obtained 4-[7-(2-butynyl)-3-(2,2-dimethylpropionyloxymethyl)-1-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in a solvent mixture of tetrahydrofuran (1.0 ml) and methanol (0.5 ml), sodium hydride (5 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2 N hydrochloric acid, and extracted with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation. The obtained residue was dissolved in N,N-dimethylformamide (1 ml), and potassium carbonate (10 mg) and methyl bromoacetate (10 μl) were added to the solution. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, and washed with water. After the organic layer was concentrated by distillation, the residue was dissolved in trifluoroacetic acid (0.5 ml), and the solution was stirred at room temperature for 30 minutes. After removing the solvent by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 6.2 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:19][CH2:16][C:3]1[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1c(Cl)cccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cccc(OCc2ccccc2)c1CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {2-chloro-6-[(phenylmethyl)oxy]phenyl}methanol (for a preparation see Intermediate 7) (1.1 g, 4.42 mmol) in DCM (12 ml) at 0-5° C. under nitrogen was added dropwise a solution of phosphorus tribromide (0.417 ml, 4.42 mmol, Aldrich) in DCM (3 ml). The solution was allowed to warm to ambient temperature and stirred for 3 h. The solution in an ice-water bath was diluted with dichloromethane (40 ml) and then treated with saturated aqueous sodium hydrogen carbonate (20 ml). The phases were separated and the organic extract dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a yellow oil (0.829 g); LCMS: (System 1) (M-H)−=311, tRET=3.84 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH2:8][CH:9](OS(C(F)(F)F)(=O)=O)[C:4]=2[CH:3]=[CH:2]1.C([O-])([O-])=O.[Na+].[Na+].CO[CH2:26][CH2:27][O:28][CH3:29]>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>[CH3:29][O:28][C:27]1[CH:5]=[CH:4][C:3]([C:9]2[C:4]3[CH:3]=[CH:2][S:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)=[CH:2][CH:26]=1
Reactant: COCCOC
Reactant: O=S(=O)(OC1CC=Cc2sccc21)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc3sccc23)cc1

Procedure:
A mixture of trifluoromethanesulfonic acid 4,5-dihydro-1-benzothiophene-4-yl ester (9.0 g, 31.7 mmol), Na2CO3 (39.6 ml 2 N aqueous, 79.2 mmol), Pd(PPh3)4 (1.83 g, 1.6 mmol), 4-methoxyboronic acid (5.78 mg, 38.03 mmol), and ethylene glycol dimethyl ether (350 ml) was heated to reflux for 6 h. The reaction was cooled, diluted with EtOAc and the layers separated. The organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 5.0 g solid (1.44:1 ratio of desired to [6,7,6′,7′-tetrahydro-[4,4′]bi[benzo[b]thiophenyl]). This material was dissolved in toluene (50 ml) and activated MnO2 (4.5 g) was added. The mixture was refluxed overnight, cooled, filtered, and concentrated to afford a 5 g solid (1.4:1 ratio of [4,4′]bi[benzo[b]thiophenyl] to desired). Column chromatography (3:97 EtOAc/hexanes) managed to isolate 880 mg of pure product: 1H NMR (300 MHz, DMSO-d6): δ 3.83 (3H, s), 7.09 (2H, d, J=8.6 Hz), 7.33 (1H, d, J=7.2 Hz), 7.40–7.45 (2H, m), 7.51 (2H, d, J=8.7 Hz), 7.79 (1H, d, J=5.5 Hz), 7.99 (1H, d, J=8.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=1[N+:22]([O-])=O)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:22]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1-c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1cccc(N)c1-c1c(N)cccc1N

Procedure:
The reaction of Step 2 is specifically performed as follows. The Pd/C of 5-15%, and preferably 10%, relative to the mass of the substrate, is added as the catalyst to the 2,2′,6,6′-tetranitrobiphenyl. The hydrogen gas of 5-20 atm, and preferably 10 atm, is added to the autoclave. Upon completion of the reaction, the solid is filtered off, and the filtrate is concentrated, to afford the 2,2′,6,6′-tetraminobiphenyl.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([Cl:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:26][CH:25]=1)[CH2:15]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Reactant: C#CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(C)NC(C)C
Product: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(Oc4ccccc4)cc2)C3=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.046 mL, 0.3 mmol), 5-bromo-7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.23 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.075 g, 71%).